ArticlePDF AvailableLiterature Review

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

September 2013
Nature Reviews Immunology 13(10)

September 2013
13(10)

DOI:10.1038/nri3523

Source
PubMed

Authors:

Christian Kurts

University of Bonn

Ulf Panzer

University of Hamburg

Hans-Joachim Anders

Ludwig-Maximilians-University of Munich

Andrew J Rees

Medical University of Vienna

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.

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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

otherorgans.

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.

1Institutes of Molecular

Medicine and Experimental

Immunology (IMMEI),

Rheinische Friedrich-

Wilhelms-Universität,

Sigmund-Freud-Str. 25,

53105 Bonn, Germany.

2III. Medizinische Klinik,

Universitätsklinikum

Hamburg-Eppendorf,

Martinistrasse 52,

20246 Hamburg, Germany.

3Medizinische Klinik und

Poliklinik IV, Ludwig-

Maximilians Universität

München, Ziemssenstr. 1,

80336 München, Germany.

4Clinical Institute of Pathology,

Medical University of Vienna,

Währinger Gürtel 18–20,

A-1090 Vienna, Austria.

e-mails: ckurts@web.de;

panzer@uke.de;

hjanders@med.uni-

muenchen.de; andrew.rees@

meduniwien.ac.at

All authors contributed

equally to this work.

doi:10.1038/nri3523

Published online

16 September 2013

The immune system and kidney

disease: basic concepts and clinical

implications

Christian Kurts1, Ulf Panzer2, Hans-Joachim Anders3 and Andrew J.Rees4

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.

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AOP, published online 16 September 2013; doi:10.1038/nri3523

Nephrons

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.

Glomerulus

An anatomical structure that

is located in the kidney cortex

and that filters blood into the

tubular system.

Tubulointerstitium

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-

cytes1–4. DCs are restricted to the tubulointerstitium and

are absent from the glomeruli1,2. In mice, kidney DCs

are CD11c+CD11b+F4/80+CX3CR1+CD8−CD205− and

have a transcriptome that is typical of DCs resident

in various non-lymphoid tissues5,6. 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)7. Kidney DCs function as sentinels

in homeostasis, local injury and infection3,8. They rap-

idly produce neutrophil-recruiting chemokines dur-

ing bacterial pyelonephritis, which is the most prevalent

kidney infection8. Neutrophils can also be recruited by

tubular epithelial cells, but not as quickly as by DCs.

Mice lacking expression of CX3C-chemokine recep-

tor1 (CX3CR1) have a selective reduction in kidney

DC numbers9. There is also a high renal expression of

its ligand CX3C-chemokine ligand 1 (CX3CL1)10, which

suggests that the CX3CR1–CX3CL1 chemokine pair

are important for DC recruitment to the kidney and

that CX3CR1 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 cytokines11,12.

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 unclear13. Macrophages

are preferentially found in the renal medulla and cap-

sule1 and have homeostatic and repair functions14.

There are also mast cells in the kidney tubulointer-

stitium but their function is poorly understood15–17.

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 inflammation18,19.

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-

tion20. 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

Kidney

Mesangial

cell

Podocyte

Bowman’s capsule

Bowman’s

space

Nephron

Endothelial

cell

Tubular

epithelial

cell

Glomerular

basement

membrane

Parietal

epithelial

cell

Proximal

convoluted

tubule

Ureter

Distal

convoluted

tubule

Glomerulus

Loop of

Henle

Ureter

Collecting

duct

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Tubules

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

nephron.

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

regulation.

Uraemia

End-stage chronic kidney

disease, the treatment of

which requires dialysis or

kidney transplantation.

Glomerulonephritis

A heterogeneous group of

immune-mediated kidney

diseases that initiate in the

glomeruli.

Podocyte

A visceral epithelial cell

that covers the glomerular

capillaries in the Bowman’s

capsule. Podocytes are a

component of the glomerular

filtration barrier.

Fibrocytes

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cells21.

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 tubulointerstitium22–24.

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 membrane25; destruction of glomerular

capillaries might restrict the perfusion of their downstream

tubulointerstitial capillaries and cause ischaemia26; pro-

inflammatory cytokines from inflamed glomeruli might

perfuse the tubulointerstitial capillaries and cause inflam-

mation27; reabsorption of abnormal amounts of protein

from the glomerular filtrate might induce stress responses

in tubular epithelial cells28; and glomerular antigens might

reach DCs in the adjacent tubulointerstitium, which in

turn might stimulate infiltrating Tcells to produce pro-

inflammatory cytokines19. 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-

cytes29. 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

syndrome

•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

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Toxins, ischaemia and trauma

Activation

Renal

tissue

Apoptosis Necrosis

PRR

PRR-expressing

renal cell

Dendritic cell Endothelial cell Tubular epithelial cellPodocyte

DAMP

Macrophage Mesangial cell

• Antigen

presentation

• Migration

• Type I IFNs, CXCL2,

IL-1β and IL-12

Acute kidney injury

and infections

• Permeability

• TNF, IL-6, chemokines

and IFNα

• ↑ Adhesion

molecules

IC-GN, diabetes and

HUS

• Permeability

• TNF, IL-6 and

chemokines

• Proteinuria

Most glomerular

diseases

• Permeability

• TNF, IL-6 and

chemokines

• Proteinuria

Acute kidney injury

and late-stage GN

• ROS, IL-1β,

TNF, IL-6 and

chemokines

Most kidney

diseases

• TNF, IL-6,

chemokines

and IFNα

IC-GN,

diabetes and

sepsis

Inflammasome

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 remodelling30–33. 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 inflammation34.

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 injury35–37. Another important DAMP is ATP

that triggers sterile inflammation in the kidneys via

the NLRP3 inflammasome38. By contrast, adenosine

receptor A2a signalling inactivates DCs and abrogates

kidney injury39. 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.

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Haemolytic uraemic

syndrome

(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).

Thrombotic

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 kidney31.

The initial inflammatory response is amplified by infil-

trating neutrophils and later by LY6Chi macrophages,

which results in acute kidney injury. The cellular

pathophysiology of ischemic acute kidney injury has

recently been reviewed by others40.

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 inflammation41. 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 DCs34.

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 debate33,42. 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) signalling43–45. 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 kidneys46.

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 manner47,48. 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 deposition49,50. 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 proteins51–54.

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)55–57.

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

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Anti-neutrophil cytoplasmic

antibody

(ANCA). An autoantibody

that is commonly found in

pauci-immune focal necrotizing

glomerulonephritis.

Crescentic

glomerulonephritis

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.

Delayed-type

hypersensitivity

(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 microvasculature58. This can be prevented

by treatment with a C3a receptor antagonist in a mouse

model of STEC-HUS58. Children with STEC-HUS have

complement hyperactivation59, and early reports docu-

ment marked improvement in small numbers of patients

shortly after treatment with eculizumab60. 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 aHUS61. Interestingly, the same mutations underlie

C3glomerulopathy (see above). Eculizumab has become

the first-line therapy in aHUS62. How similar and/or

identical defects in regulatory proteins of the alternative

complement pathway lead to a range of phenotypical

manifestations of systemic and renal disease remains to

be fully elucidated.

TTP has been linked to reduced activity of a disintegrin

and metalloproteinase with thrombospondin motifs13

(ADAMTS13), which results from either genetic or a

cquired defects, including the generation of ADAMTS13-

specific autoantibodies. Reduced ADAMTS13 activity

leads to the disruption of vonWillebrand factor-multi mer

processing, the development of platelet thrombi and

microvascular injury63.

The major advances in the field of C3 glomerulopathy

and thrombotic microangiopathies now provide the basis

for a new pathogenesis-based disease classification, and

complement dysregulation is likely to be a general feature

in all of these disease entities. Most importantly, this gain

in understanding has resulted in the use of terminal com-

plement inhibition as a first-line therapy in aHUS, and

might also result in its use in the other forms of HUS in

certain circumstances in the future61. Moreover, hyperac-

tivation of C5a and its receptor may also be involved in

other renal autoimmune diseases such as anti-neutrophil

cytoplasmic antibody (ANCA)-associated vasculitis64.

Tcell responses targeting the kidney

DTH in crescentic glomerulonephritis. Glomerular cres-

cents, formed by proliferation of the glomerular pari-

etal epithelial cells and infiltrating leukocytes, are the

morphological hallmarks of the most aggressive form of

glomerulonephritis that progresses rapidly towards kid-

ney failure. Despite being first described 100years ago,

nephrotoxic nephritis remains one of the most widely

studied mouse models of crescentic glomerulonephritis.

It is induced by injecting mice with heterologous anti-

bodies specific for the glomerular basement membrane

(GBM) (Supplementary information S1 (table)). Injury

in this model was initially thought to be exclusively

mediated by antibodies65. Subsequent studies sug-

gested that there might also be roles for antigen-specific

Tcells66–68, and Holdsworth and colleagues69 established

that Tcell-dependent delayed-type hypersensitivity

(DTH) responses to the heterologous immunoglobulins

deposited in the kidney were an underlying mechanism

of injury (FIG.2).

Recent studies showed the following sequence of

events to take place. In the first days following anti-

body injection, innate immune cells, including neutro-

phils, mast cells15 and interleukin-17 (IL-17)-producing

γδTcells70, mediate renal damage. Tcells specific for

the heterologous antibodies are simultaneously primed

in the lymphatic tissues and start entering the kidneys.

A first wave of T cells, starting 4days after nephritis

induction, consists of pathogenic T helper 17 (TH17)

cells expressing CC-chemokine receptor 6 (CCR6)

and retinoic acid receptor-related orphan receptor-γt

(RORγt)71-74. Their activity is controlled by CXC-

chemokine receptor 6 (CXCR6)-expressing regula-

tory invariant natural killer T (iNKT) cells, which

are recruited by immature renal DCs secreting CXC-

chemokine ligand 16 (CXCL16)75. If inflammation fails

to resolve, renal DCs eventually mature and recruit

CXCR3+ TH1 cells by producing CXCL9 (REFS76,77).

TH1 cells encounter antigens presented by DCs in

the context of upregulated co-stimulatory molecules

and IL-12. Next, activated TH1 cells recruit more pro-

inflammatory cells, including monocytes and fibro-

cytes29, and stimulate mannose receptor-dependent

macrophages78 to produce injurious mediators such as

tumour necrosis factor (TNF) and nitric oxide69,72. As

renal DCs are located in the interstitium but not within

the glomeruli, the stimulation of TH1 cells takes place in

the periglomerular space, adjacent to parietal epithelial

cells. The proliferative response of parietal epithelial

cells and immune cells contributes to the characteristic

glomerular crescents. CCR6+ and CCR7+ regulatory T

(TReg) cells may still be able to control inflammation at

this stage79–81. The severity of the initial injury deter-

mines the balance between pro-inflammatory and

anti-inflammatory Tcells in the tissue, and whether

kidney disease resolves or progresses to fibrosis. After

14days, host antibodies that have been raised against

the heterologous antibodies increasingly contribute to

kidneyinjury.

Although immunity in nephrotoxic nephritis is

directed against a different antigen than in human

crescentic glomerulonephritis, this model has been

instrumental in elucidating the mechanisms that drive

immune responses to glomerular antigens and has made

crucial contributions to the design of novel therapies.

However, the extent to which DTH is also responsi-

ble for human crescentic glomerulonephritis remains

uncertain. Furthermore, it would be desirable to study

whether these cellular immune mechanisms are also

relevant in other forms of glomerulonephritis.

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Nature Reviews | Immunology

IL-23R

Neutrophil

Renal cell inﬁltration Renal cell inﬁltration

γδ T cell TH17 cell DC

CCR6

CCR2

Pro-inﬂammatory responses

Anti-inﬂammatory responses

IL-17?

TH1 cell

CXCR3 CCR2

CX3CR1

Macrophage

TNF and

nitric oxide

IFNγ

Autologous

antibodies

Regulatory

iNKT cell

Immature DC

Acute inﬂammation

Day 4

CXCR6 CCR6

CCR7

IL-4 and

IL-10

CXCL16

TReg cell

1 week 2 week Months?

IL-10 and

PDL1

Irreversible ﬁbrosis

Glomerular

sclerosis

Tubulointerstitial

ﬁbrosis

Fibrosis

Kidney

injury

Tcell-mediated glomerular injury. The role of Tcells

in renal injury has long been controversial65–67. A recent

study using transgenic mice showed that adoptively trans-

ferred CD4+ TH cells and cytotoxic CD8+ Tcells that are

specific for glomerular antigens can injure the kidneys19.

The resulting release of glomerular antigens starts a

vicious circle involving antigen capture and presentation

by renal DCs to TH cells, the production of chemokines

and cytokines, the recruitment of more CD8+ Tcells

and macrophages, and increased renaldamage.

These findings, together with those in nephro-

toxic nephritis, emphasize the importance of crosstalk

between mature renal DCs and TH cells; in both cases

the removal of kidney DCs in mice by depletion19,82, by

CX3CR1 blockade or by genetic knockout9,83 rapidly

reduced the mononuclear cell infiltration and halted

disease progression. Although the route by which glo-

merular antigens reach DCs in the tubulointerstitium

is still unclear, their ability to do so and to stimulate

TH cells may contribute to the spreading of glomerular

Figure 2 | Cellular immune response in experimental crescentic glomerulonephritis. The time-dependent changes

in the pro-inflammatory and anti-inflammatory functions of leukocyte subsets during the course of experimental crescentic

glomerulonephritis (a nephrotoxic nephritis model) are shown. a | The clinical outcome of the disease mainly depends on

the balance between pro-inflammatory and anti-inflammatory immune cells. Whether this concept is relevant to human

crescentic glomerulonephritis remains to be shown. Neutrophil recruitment to the kidney starts several hours after the

induction of nephrotoxic nephritis and is partly mediated by interleukin-17A (IL-17A)-producing γδ Tcells, which are

activated by IL-23. The adaptive immune response is initiated by mature dendritic cells (DCs) that depend on CX3C-chemokine

receptor1 (CX3CR1) and CC-chemokine receptor 2 (CCR2). At earlier stages, immune responses that are mediated by

CCR6‑expressing Thelper 17 (TH17) cells predominate, whereas at later stages, CXC-chemokine receptor 3 (CXCR3)+

TH1 cells are the prevailing mediators of renal tissue injury, as they produce cytokines such as interferon-γ (IFNγ), which

activate macrophages. In addition, host antibodies against the heterologous antibodies form intrarenal immune complexes

and thereby contribute to renal tissue damage. During the first days immature DCs attenuate crescentic glomerulonephritis

by attracting regulatory invariant natural killer T (iNKT) cells via the CXC-chemokine ligand 16 (CXCL16)–CXCR6 axis, and

these cells produce IL-4 and IL-10 and thereby might reduce the destructive TH1 and TH17 cell responses. At a later stage,

CCR6+ and CCR7+ regulatory T (TReg) cells are recruited into the inflamed kidney and protect against an overwhelming

TH1cell‑ and TH17 cell-mediated immune response, at least partly through the local production of IL-10 and the expression

of programmed cell death 1 ligand 1 (PDL1). b | Periodic acid-Schiff (PAS) staining of kidney sections from patients with

acute crescentic glomerulonephritis shows glomerular and tubulointerstitial leukocyte infiltration. Irreversible kidney

damage occ urs along with glome rular sclerosis and tubulointerstitial fibrosis when the inflammatory response persists.

IL-23R, IL-23 receptor; TNF, tumour necrosis factor. Image courtesy of U. Helmchen, Hamburg, Germany.

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Proteinuria

The urinary loss of protein,

which has numerous clinical

consequences. Proteinuria is

also used as a biomarker for

renal filter dysfunction.

Anti-GBM disease

(Anti-glomerular basement

membrane disease; also known

as Goodpasture’s disease).

A severe form of crescentic

glomerulonephritis caused

by autoantibodies that are

specific for the NC1 domain of

the α3 chain of typeIV collagen

(α3(IV)NC1) in the GBM.

Membranous nephropathy

A glomerulonephritis form

characterized by the

subepithelial deposition of

secretory phospholipase A2

receptor (PLA2R)-specific

antibodies, which leads to

podocyte injury and heavy

proteinuria. It is the most

common cause of the

nephrotic syndrome in adults.

Nephrotic syndrome

A syndrome characterized

by heavy proteinuria,

hypoalbuminaemia and

a loss of immunoglobulins,

which results in humoral

immunodeficiency, oedema,

hyperlipidaemia and

thrombosis. This syndrome

results from damage to the

glomerular filter, which

causes the loss of proteins

above 50 kDa in size from

the circulation.

injury to the tubulointerstitium68, and therefore may

represent a mechanism of kidney disease progression.

However, the relevance of these immune mechanisms

for human glomerulonephritis remains to be shown. In

particular, the role of cytotoxic T lymphocytes (CTLs)

in human nephritis is unclear. In addition, the (auto)

antigens presented to TH cells remain to be identified.

Finally, intrinsic renal cells, such as glomerular podo-

cytes84 and tubular epithelial cells85, can also present anti-

gen to Tcells, but the invivo relevance of these processes

is unclear.

Proteinuria. Damage to the glomerular filtration bar-

rier causes protein to leak into the glomerular filtrate,

which results in abnormally high concentrations in the

urine: this is known as proteinuria. Proteinuria can itself

cause injury, which is mediated either by the properties

of specific proteins in the filtrate or simply through the

mass of filtered protein; for example, fibrin can induce

the proliferation of parietal glomerular epithelial cells

and thus can aggravate crescentic glomerulonephritis86.

Increased protein in tubular fluid enhances reabsorption

by the tubular epithelial cells and can overload their cata-

bolic capacity, which results in a lysosomal burst and the

release of cathepsins into the cytoplasm28. Filtered com-

plement components, especially properdin (also known

as factor P), contact the tubular epithelial cells and acti-

vate the alternative complement pathway that damages

tubular cells87,88. Tubulointerstitial DCs capture filtered

proteins, either directly or from tubular cells, and use

them to locally stimulate infiltrating CTLs or TH cells82,89.

Such presentation of antigens that would normally be

ignored may contribute to the infiltration of immune

cells into the tubulointerstitium and to the progression

of renal disease, but the relevance of this mechanism to

human kidney disease remains to be shown. Regardless

of the mechanisms involved, non-specifically reducing

proteinuria — for example, by lowering glomerular fil-

tration pressure by the pharmacological inhibition of the

renin–angiotensin system — has become an important

therapeutic concept.

Antibody-dependent kidney diseases

Rodent studies have increased our understanding of

the nature of the immune responses in the kidneys and

how they are subverted to cause injury. Furthermore, the

examination of the patterns of immunoglobulin depo-

sition in the kidneys initiated the ultimately successful

search for autoantibodies in human anti-GBM disease and

membranous nephropathy and lead to the characterization

of the glomerular antigens they recognize.

Anti-GBM disease. Anti-GBM disease, formerly known

as Goodpasture’s disease, is a severe form of crescentic

glomerulonephritis that is caused by autoantibodies

specific for the non-collagenous 1 (NC1) domain of

the α3 chain of typeIV collagen (α3(IV)NC1) in the

GBM90,91. TypeIV collagen in the GBM consists of α3, α4

and α5 chains, the NC1 domains of which form hexam-

ers that are stabilized by sulfilimine bonds92. Pathogenic

autoantibodies bind to two dominant epitopes on the

α3(IV)NC1 domain (EA-α3 and EB-α3), and to a

homologous epitope on the α5(V1)NC1 domain

(EA-α5)92. Although they are freely accessible in indi-

vidual NC1 domains, all three epitopes are hidden in

the hexamers and so are unavailable for antibody bind-

ing in the intact GBM. A conformational change in

NC1 hexamers within the GBM is required to expose

the epitopes and to facilitate autoantibody binding,

which then amplifies further conformational changes

and autoantibody binding. This may be an explana-

tion for the rapid development of the injury in this

disease. By contrast, GBM-specific alloantibodies that

develop after transplanting a normal kidney into α5(IV)

NC1-deficient mice recognize epitopes on the surface

of the NC1 hexamer and bind to them without the need

for conformational change93.

Susceptibility to anti-GBM disease is strongly influ-

enced by the HLA classII haplotype: over 80% of those

affected carry the HLA-DRB1*15:01 allele94. The direct

involvement of HLA-DRB1*15:01 in the specific auto-

immune response to α3(IV)NC1 has been confirmed

invitro using human Tcells95,96 and in transgenic mice

that only express HLA-DRB1*15:01 (REF. 97). The natu-

rally processed α3(IV)NC1 peptides that were bound

to HLA-DRB1*15:01 on antigen-presenting cells have

been characterized98 but Tcells from patients with anti-

GBM disease fail to respond to them. These peptides are

fairly resistant to antigen-processing enzymes, whereas

the four epitopes that are commonly recognized by the

patients’ Tcells are rapidly digested95,96. This may be an

explanation as to why NC1-specific autoreactive Tcells

in patients with this disease escape thymic deletion.

Rodent models of autoimmune anti-GBM disease

resemble the human clinical disease and are driven by

similar α3(IV)NC1 epitopes90,97, but DTH rather than

antibodies cause the severe injury, at least in mice81,91. It

remains to be seen whether the contribution of DTH to

injury in anti-GBM disease has been underestimated in

humans; indeed, TH1 cells that are specific for α3(IV)NC1

predominate in the acute phase of anti-GBM disease

in humans but they are replaced by an antigen-specific

IL-10-producing TReg cell response that coincides with a

reduction in anti-GBM antibody levels and with reduced

disease activity90,95.

PLA2R-specific antibodies in membranous nephropa-

thy. Membranous nephropathy is a major cause of glo-

merulonephritis with nephrotic syndrome in adults. It is

characterized by the thickening of the GBM and the

deposition of immune complexes between the mem-

brane and the podocytes. Approximately 75% of cases

are idiopathic and 25% are secondary to a wide range

of causes, including neoplasia, infections, drugs and

systemic autoimmune disease. Classic studies using the

Heymann nephritis model of membranous nephropa-

thy (Supplementary information S1 (table)) showed that

circulating antibodies that are specific for megalin (also

known as LRP2) — a protein that is expressed on the

surface of glomerular podocytes — promote the forma-

tion of immune complexes in the kidneys99. However,

human podocytes lack megalin.

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IgA nephropathy

The most common form of

glomerulonephritis worldwide.

It is characterized by the

deposition of IgA-containing

immune complexes in the

mesangial compartment of

glomeruli, which leads to

mesangial cell-proliferative

lesions, haematuria and

proteinuria.

Pauci-immune focal

necrotizing

glomerulonephritis

(Pauci-immune FNGN).

A highly inflammatory form

of glomerulonephritis in which

glomerular immune complex

deposits are absent or scarce.

It is commonly associated with

small vessel vasculitis and with

anti-neutrophil cytoplasmic

antibodies.

NETosis

The formation and the release

of neutrophil extracellular

traps (NETs) by activated

neutrophils to ensnare

invading microorganisms.

NETs enhance neutrophil killing

of extracellular pathogens

while minimizing damage to

the host cells.

Humanized mice

Immunodeficient mice that

are engrafted with human

haematopoietic cells or tissues,

or mice that transgenically

express human genes.

The autoantigen in human idiopathic membra-

nous nephropathy was recently identified as secretory

phospholipase A2 receptor (PLA2R; also known as

CLEC13C) on podocytes100. PLA2R-specific auto-

antibodies, usually of the IgG4 subclass, were found in

the serum of 50–70% of patients with primary mem-

branous nephropathy. Subsequent studies showed that

the levels of PLA2R-specific autoantibodies correlate

with the level of proteinuria and could possibly be used

to predict clinical outcome100 and disease recurrence

after renal transplantation101. So far, there is no proof

that PLA2R-specific autoantibodies are pathogenic,

but a genome-wide association study has shown that

PLA2R1 polymorphisms influence susceptibility to idio-

pathic membranous nephropathy102. This study also

confirmed that there is a strong association between the

disease and certain HLA-DQA1 alleles, which suggests

that these HLA classII molecules may facilitate autoim-

munity against PLA2R102. However, as only 50–70% of

patients with primary membranous nephropathy have

PLA2R-specific autoantibodies, additional autoantigens

remain to be identified. Moreover, the pathophysiological

role of PLA2R-specific autoantibodies is still unknown.

IgA nephropathy. IgA nephropathy is the most common

primary form of glomerulonephritis and is an impor-

tant cause of kidney failure. Recent studies suggest that

a multistep process is involved in the immunopatho-

genesis of this disease. Bcells from patients with IgA

nephropathy produce aberrantly glycosylated IgA103,

possibly as a consequence of the aberrant homing of

mucosal Bcells to the bone marrow, where they syn-

thesize under-galactosylated IgA. Patients with IgA

nephropathy develop autoantibodies against under-

galactosylated IgA, which might also cross-react with

mucosal microbial antigens, although this has not been

formally shown. These autoantibodies form immune

complexes in the circulation, which are then deposited in

the glomerular mesangium by mechanisms that are so far

incompletely understood104. The deposited immune com-

plexes induce the local expression of pro-inflammatory

mediators and growth factors, which activate mesangial

cells and enhance their secretion of extracellular matrix

proteins, which leads to glomerular sclerosis and loss

of renal function. The presence of IgG and IgA glycan-

specific autoantibodies was shown to correlate with

progressive disease in a large group of patients105, which

suggests that these glycan-specific autoantibodies are

potentially pathogenic. However, the factors that are

responsible for the synthesis of under-galactosylated

IgA, autoantibody generation, mesangial deposition of

immune complexes and injury remain elusive.

Lupus erythematosus. The extrarenal mechanisms

of lupus nephritis involve complex genetic variability

that compromises immune tolerance to nuclear auto-

antigens106–108. The nucleic acid components of nuclear

autoantigens support this process via their TLR-

dependent autoadjuvant effects109–111. As such, endoge-

nous nuclear particles are handled as viral particles and

induce interferon-α signalling112,113, which is similar to

viral infections114,115. The link between systemic lupus

erythematosus and lupus nephritis is the production

of autoantibodies that bind to autoantigens in the kid-

neys; for example, a subset of double-stranded DNA

(dsDNA)-specific antibodies cross-react with annexin II

on the cell surface, in the cytoplasm and in the nucleus of

mesangial cells116, and also cross-react with nucleosomes

in the mesangium and in the glomerular capillary epi-

thelium117. The extent and the progression of glomeru-

lar immunopathology depends on the site of immune

complex formation, as this determines the predominant

glomerular cell type that is affected118 (FIG.3).

Pauci-immune focal necrotizing glomerulonephritis.

Pauci-immune focal necrotizing glomerulonephritis (FNGN)

is a systemic autoimmune disease that is characterized

by crescentic glomerulonephritis. It typically occurs

in the context of systemic small vessel vasculitis and

autoantibodies that bind to neutrophil cytoplasmic

antigens specific for either myeloperoxidase (MPO) or

proteinase 3 (PR3; also known as myeloblastin)119. Most

patients with pauci-immune FNGN also have autoan-

tibodies to lysosome-associated membrane glycopro-

tein2 (LAMP2)120,121, although the frequency of these

antibodies is controversial122. All three target antigens

are released into injured glomeruli by infiltrating neutro-

phils after degranulation or through NETosis123. LAMP2 is

also expressed on the surface of the glomerular endothe-

lium108. Injury is thought to be autoantibody mediated,

not least because Bcell ablation with rituximab is a highly

effective treatment for pauci-immune FNGN119 (TABLE1).

Despite this, deposits of immunoglobulin and comple-

ment components in pauci-immune FNGN are small and

restricted to necrotic areas of the kidneys. The role of

complement is being re-evaluated in PhaseI clinical trials

of complement inhibitors because patients with clinically

active disease have systemic complement activation124,125.

Finally, there is evidence that cell-mediated immunity is

also involved126: lymphocytes infiltrate the glomeruli and

the tubulointerstitium127, and there are circulating MPO-

specific and PR3-specific TH1 and TH17 cells in patients

with pauci-immune FNGN126. Furthermore, CD8+ Tcells

are increased and express a transcriptomic signature that

correlates with the risk of disease relapse128.

Clinical119 and genetic129 studies combined with

invitro experiments130 and rodent models131 provide

compelling evidence that MPO-specific and PR3-specific

autoantibodies can be pathogenic. Mice that have been

injected with antibodies specific for MPO develop pauci-

immune FNGN, although injury is mild in most mouse

strains unless the antibody is administered together with

a neutrophil-activating factor such as TNF, C5a or IL-1

(REFS130,131 ). This facilitates binding of the antibodies

to circulating neutrophils and promotes their glomeru-

lar localization with the release of MPO132. Attempts to

induce pauci-immune FNGN in mice with PR3-specific

antibodies have been unsuccessful130,131, except in a sin-

gle report in which PR3-specific autoantibodies from a

patient with pauci-immune FNGN were injected into

humanized mice133. This possibly reflects the differences in

PR3 expression by human and mouse neutrophils125,131.

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Subepithelial immune

complex deposits

• Podocyte injury

• Large proteinuria

• Membranous

nephropathy

– Primary (PLA2R)

– Secondary (lupus

nephritis class V)

Linear immune complex

deposits

• Endothelial cell and

podocyte injury

• CKD, proteinuria and

haematuria

• Anti-GBM disease

Mesangial immune complex

deposits

• Mesangial cell injury

• Asymptomatic proteinuria

and microscopic haematuria

• IgA nephropathy and lupus

nephritis class I and II

C3 deposition

• Glomerular cell injury

• Asymptomatic

proteinuria and

microscopic haematuria

• C3 glomerulopathy and

aHUS

Pauci-immune

• Vascular necrosis

• CKD, proteinuria and

haematuria

• Focal necrotizing

glomerulonephritis

and ANCA-associated

vasculitis

Subendothelial immune

complex deposits

• Endothelial cell injury

• CKD, proteinuria and

haematuria

• Lupus nephritis class III

and IV

PLA2R-speciﬁc

antibodies

α3(IV)NC1-

speciﬁc

antibodies

PR3

LAMP2

Neutrophil

MPO

ANCA

Mesangial

cell

Endothelial

cell

Podocyte

foot process

Antibodies that are specific for recombinant human

LAMP2 bind to the glomerular endothelium and cause

pauci-immune FNGN when they are injected into

Wistar-Kyoto rats120.

Mice that have been immunized with MPO develop

autoantibodies and DTH responses characterized by

TH1 and TH17 cells, but they remain healthy even in the

absence of autoimmune regulator (AIRE) — which is

expressed by medullary thymic epithelial cells and which

promotes the expression of tissue-specific antigens

(including MPO) that regulate central tolerance to these

antigens — and despite the abundance of MPO in thymic

myeloid cells134,135. Mice with autoimmunity to MPO

remain healthy but develop severe pauci-immune FNGN

in response to injection of GBM-specific antibodies at

levels below the threshold required to cause kidney tissue

Figure 3 | Local immune pathways in glomerulonephritis. Glomerular immunopathology often develops from

intraglomerular complement activation via the classical (immune complex-related) or alternative (immune complex-

independent) complement pathway. Immune complexes can form in different compartments of the glomerulus, which

determines the resulting histopathological lesion, as different glomerular cell types are primarily activated in each

compartment. The resulting histopathological lesions determine the classification of glomerulonephritis. Immune

complex deposition in the mesangium activates mesangial cells, which leads to mesangioproliferative glomerulopathies,

such as IgA nephropathy or lupus nephritis classI and II. Subendothelial immune complex deposits activate endothelial

cells, as seen in lupus nephritis classIII and IV. Subepithelial immune complex deposits preferentially activate the

visceral glomerular epithelium — that is, podocytes — and usually cause massive proteinuria, as these cells are

essential for the glomerular filtration barrier. As a result of the poor regeneration of podocytes compared with that

of the other glomerular cell types, podocyte loss leads to progressive membranous nephropathy and end-stage renal

disease. Primary membranous nephropathy mainly develops from autoimmunity against PLA2R, whereas secondary

forms of this nephropathy represent renal manifestations of systemic disorders such as lupus nephritis. Hence, the level

of proteinuria is an important prognostic biomarker and predictor of poor outcomes of glomerulopathies. Linear

immune complex deposits indicate antibody binding to autoantigens within the glomerular basement membrane (GBM),

for example, collagen IV antibodies in anti‑GBM disease. Anti-neutrophil cytoplasmic antibody (ANCA)-associated

glomerulonephritis develops in the absence of immune complex deposits (known as pauci-immune), as it is driven by

both ANCAs and cellular immunity. Complement component C3 glomerulopathies and atypical haemolytic uraemic

syndrome (aHUS) develop from the aberrant activation of the alternative complement pathway. The boxes list in

order the type of immune deposits, the glomerular structure that is primarily affected, the dominant clinical signs

and the related disorders for each mechanism. α3(IV)NC1, non‑collagenous 1 (NC1) domain of the α3 chain of typeIV

collagen; CKD, chronic kidney disease; LAMP2, lysosome-associated membrane protein 2; MPO, myeloperoxidase;

PLA2R,secretory phospholipase A2 receptor; PR3, proteinase 3.

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Table 1 | Implementation of immunosuppressive or anti-inflammatory therapies in the treatment of kidney diseases

Target Drugs Effective in animal kidney

disease models?

Effective in human kidney disease?

IL-1 IL-1-specific antibody or

recombinant IL-1RA

Oxalate nephropathy, IgA

nephropathy and anti-GBM

disease

Unknown

IL-6 IL-6-specific antibody Lupus nephritis, anti-GBM

disease and immune complex

glomerulonephritis

Unknown

IL-17 IL-17-specific antibody Crescentic glomerulonephritis Unknown

TNF TNF-specific antibody

TNFR–Fc fusion protein

Lupus nephritis, anti-GBM and

ANCAs, glomerulonephritis,

glomerulosclerosis and acute

kidney injury

•TNF-specific antibody was effective in severe lupus nephritis,

but had side effects

•The TNF inhibitor etanercept (Enbrel; Amgen/Pfizer) was not

effective in ANCA-associated vasculitis

TGFβTGFβ-specific antibody

that blocks TGFβ1

Renal scarring in diabetic

nephropathy

Clinical trials ongoing (NCT01113801*)

TWEAK TWEAK-specific

antibody

Lupus nephritis, lipid

nephropathy and crescentic

glomerulonephritis

Clinical trial ongoing in lupus nephritis (NCT01499355*)

CCR2 CCR2 antagonist Diabetic nephropathy,

hypertensive nephropathy and

crescentic glomerulonephritis

Clinical trial of ongoing in diabetic nephropathy (NCT01447147*)

CCR5 CCR5 antagonist Immune complex

glomerulonephritis and allograft

rejection

Unknown

TLR2 TLR2-specific antibody Acute kidney injury Clinical trial in delayed-kidney allograft function ongoing

(NCT01794663*)

Thymocytes Anti-thymocyte

globulin

Numerous immune disorders Kidney allograft rejection and graft-versus-host disease

Lymphocytes Anti-lymphocyte

globulin

Numerous immune disorders Kidney allograft rejection and graft-versus-host disease

CD52 (on

mature

lymphocytes)

CD52-specific

monoclonal antibody

Numerous immune disorders Clinical trials ongoing in ANCA-associated vasculitis

(NCT01405807*)

IL-2R (also

known as CD25)

IL-2R-specific antibody Allograft rejection Prevention of kidney allograft rejection‡

B7-1 (also known

as CD80)

CTLA4–Fc fusion

protein

Allograft rejection and lupus

nephritis

•Prevention of kidney allograft rejection in a PhaseII clinical trial

•Negative results from a PhaseIII clinical trial is under debate and

further studies are ongoing (NCT00774852*)

CD20+ Bcells CD20-specific antibody Lupus nephritis and anti-GBM

disease

•Effective in refractory lupus nephritis (uncontrolled studies)

•Not effective in LUNAR trial as an add-on to steroids and

mycophenolate mofetil

•Effective in clinical trials for ANCA-associated vasculitis‡ (RAVE

and RITUXVAS trials)

•Beneficial in observational studies of membranous

nephropathy; controlled clinical trials ongoing (NCT01508468*;

NCT01180036*)

•Trials ongoing in steroid resistant focal glomerulosclerosis

(NCT01573533*; NCT00981838*; NCT00550342*)

BLYS (on Bcells) BLYS-specific antibody SLE, including lupus nephritis •Effective in SLE but not specifically for severe lupus nephritis

(further trials ongoing)

•Clinical trials ongoing in membranous nephropathy

(NCT01762852*; NCT01610492*)

BAFF (on Bcells) BAFF-specific antibody None reported Effective in SLE and clinical trials ongoing in lupus nephritis

(NCT01639339*)

C5 C5-specific antibody

or orally active C5aR

inhibitor

Anti-MPO FNGN Effective in atypical HUS, unclear data on effectiveness in

STEC-HUS and clinical trials ongoing in ANCA-associated

vasculitis (NCT01363388*)

ANCAs, anti-neutrophil cytoplasmic antibodies; BAFF, B cell-activating factor; BLYS, B lymphocyte stimulator; C5, complement component C5; C5aR, C5a

anaphylatoxin chemotactic receptor; CCR, CC-chemokine receptor; CTLA4, cytotoxic T lymphocyte antigen 4; FNGN, focal necrotizing glomerulonephritis;

GBM, glomerular basement membrane; HUS, haemolytic uraemic syndrome; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; MPO, myeloperoxidase;

SLE, systemic lupus erythematosus; STEC-HUS, Shiga toxin-producing Escherichia coli-induced haemolytic uraemic syndrome; TGFβ, transforming growth factor-β;

TLR, Toll-like receptor; TNF, tumour necrosis factor; TNFR, tumour necrosis factor receptor; TWEAK, TNF-related weak inducer of apoptosis. *Identifier on

ClinicalTrials.gov. ‡Treatment approved by the US Food and Drug Administration.

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Nature Reviews | Immunology

Hypoperfusion of

damaged nephrons

↑ Renin, angiotensin

and aldosterone

Uraemia and

retention of

metabolic waste

↓ Erythropoietin Renal anaemia

Immune dysregulation

and calcium and

bone loss

Intestinal barrier

dysfunction and

endotoxaemia

Loss of proteins with

immune functions (such

as immunoglobulin,

zinc-binding protein

and ferritin)

Hypertension

Immunosuppression

TH17 cell polarization

Systemic inﬂammation

Chronic

oxidative stress

Vascular damage

and atherosclerosis

Infections

DC polarization

↑ Sodium retention

↓ Vitamin D

↓ Uromodulin

↓ Protein catabolism

↓ Cytokine elimination

↑ Complement turnover

Extensive

proteinuria

injury. Unexpectedly, injury is not caused by autoanti-

bodies, as it occurs in Bcell-deficient mice134. Instead, it is

caused by DTH134, as it can be transferred by Tcells136 and

is abrogated in IL-17A-deficient mice137. Disease sever-

ity is modulated by forkhead box P3 (FOXP3)+ TReg cells,

which are induced by IL-10-producing mast cells that are

recruited to regional lymph nodes after immunization

withMPO17.

Neutrophil extracellular traps (NETs) are generated

in patients with FNGN123 and have been suggested to

initiate the synthesis of autoantibodies to MPO. This is

consistent with the observation that the delivery of NETs

to mice — either through direct injection or through

adoptive transfer of NET-pulsed DCs125 — induces

autoimmunity to MPO (and to DNA)125. However, the

administration of PR3 does not provoke pauci-immune

FNGN in rodents120,121.

The stimuli that initiate autoantibody synthesis in

pauci-immune FNGN remain unknown but have been

linked to infection since the earliest clinical descriptions

were made. Recent studies are beginning to suggest why:

nasal carriage of Staphylococcus aureus is associated with

clinical disease relapses119, and proteins that are derived

from this pathogen have been shown to induce Bcells

from patients with pauci-immune FNGN to produce

PR3-specific antibodies138. Some patients with auto-

immunity to PR3 have been reported to have anti-idio-

typic antibodies that bind to a peptide with a sequence

that is complementary to PR3 (REF.130). The comple-

mentary peptide is similar to staphylococcal and other

microbial proteins, and it has been suggested that these

proteins may function as molecular mimics. However,

these results have not been confirmed139. By contrast,

there is strong evidence for molecular mimicry between

LAMP2 and the bacterial adhesion protein FimH120.

Autoantibodies specific for LAMP2 commonly bind

to and cross-react with an epitope in FimH. Moreover,

immunization of WKY rats with FimH induces the

production of antibodies that bind to human and rat

LAMP2 and it promotes the development of pauci-

immune FNGN. This confirms the molecular mimicry

between the two molecules and suggests a pathogenic

role for LAMP2-specific autoantibodies. Detailed

prospective clinical analyses are now needed to deter-

mine the role of the molecular mimicry of LAMP2 in

pauci-immuneFNGN.

The effect of CKD on systemic immunity

The state of reduced renal function that results from

CKD causes marked alterations in the immune sys-

tem, including persistent systemic inflammation and

acquired immunosuppression140 (FIG.4). Typical altera-

tions include increased systemic concentrations of pro-

inflammatory cytokines and acute phase proteins, such

as the pentraxins, as well as dysfunctional phagocytes,

Bcells and Tcells141. The persistent systemic inflamma-

tion contributes to bone loss, accelerated atherogenesis

and body wasting, whereas the immunosuppressed state

accounts for infectious complications, which together

determine the morbidity and the mortality that is asso-

ciated with CKD. The immune dysregulation was pre-

viously attributed to the effects of haemodialysis but is

now known to precede it and to persist afterwards142.

Several recently discovered consequences of the loss of

kidney functions on immune responses are described

below, which alone, or in concert, may affect general

immunity (FIG.4).

Uraemia. CKD results in the retention of low-

molecular-mass metabolites, such as phenylacetic

acid, homocysteine, various sulfates, guanidine com-

pounds and many others. These have inhibitory effects

on immune cell activation, promote leukocyte apop-

tosis and induce the oxidative burst in phagocytes143.

Chronic oxidative stress increases protein oxidation,

which reduces the activity of enzymes, cytokines and

antibodies, contributing to both general inflammation

and immune dysfunction in CKD. Moreover, oxidized

low-density lipoproteins attract and activate granulo-

cytes, and high-density lipoproteins, which are nor-

mally anti-atherogenic, are altered to lipoproteins with

pro-atherogenic properties144.

Figure 4 | Consequences of chronic kidney disease with potential effects on

systemic immunity. Chronic kidney disease (CKD) has several immediate

consequences (blue boxes), which are proposed to result in three main immunological

alterations (red boxes) through intermediate steps. First, chronic stimulation of the

renin–angiotensin–aldosterone system causes T helper 17 (TH17) cell polarization,

through dendritic cell (DC) polarization and possibly through sodium retention.

Second, uraemic intestinal barrier dysfunction, vitaminD deficiency and cytokine

accumulation (which may be due to impaired protein catabolism, reduced uromodulin

levels and chronic oxidative stress) result in systemic inflammation. Third, systemic

immunosuppression results from the uraemic accumulation of toxic metabolic waste,

the increased turnover of the components of the alternative complement pathway

because of impaired protein catabolism, and in cases of extensive proteinuria, the

urinary loss of proteins with immunological functions. This figure also integrates the

key clinical consequences of CKD, which include hypertension, vascular damage and

atherosclerosis, renal anaemia and bone loss (in bold). These mechanisms may alone

or in concert affect general immunity.

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Uraemia affects systemic immunity by causing intes-

tinal dysbiosis and by destabilizing the intestinal bar-

rier140,145 (FIG.4). The metabolic consequences of uraemia

favour pathogen overgrowth, which can increase the

production of uraemic toxins inside the gut and can

reduce the production of immunoregulatory short-

chain fatty acids146. As in heart failure and liver cirrhosis,

uraemia-related hypervolaemia leads to intestinal wall

congestion, which impairs the intestinal wall barrier and

promotes the leakage of pathogen-associated molecular

patterns (PAMPs) into the circulation140. In fact, systemic

lipopolysaccharide (LPS) levels increase in patients with

CKD as renal function declines and are highest among

those on dialysis147. Intestinal PAMP leakage may not

only activate innate immune-mediated systemic inflam-

mation but also, paradoxically, could lead to concomi-

tant immunosuppression, through similar mechanisms

that account for endotoxin tolerance invitro and com-

pensatory anti-inflammatory syndrome in patients with

advanced sepsis148,149 (FIG.4).

Renal protein catabolism. Proteins and polypeptides with

a molecular mass below 50 kDa pass into the glomeru-

lar filtrate and are reabsorbed and catabolized by the

tubular epithelium to enable amino acids to be recycled.

They consequently accumulate in the blood of patients

with CKD, reaching concentrations more than tenfold

higher than normal in severe cases, and they have marked

effects on immune function143. Examples of these effects

include the following: an accumulation of IgG light

chains (25 kDa in size) suppresses Bcell and granulocyte

function; increased concentrations of the MHC classI

component β2 microglobulin (45 kDa in size) aggregate

into amyloid fibrils; increased concentrations of leptin

(16 kDa in size) and the granulocyte protein resistin

(12 kDa in size) diminish phagocyte function; increased

levels of complement factor D (27 kDa in size) enhance

the activity of the alternative complement pathway and

generate immunosuppressive fragments (such as the

complement factor B Ba fragment; which, as a result of

its 33 kDa size, also accumulates in CKD on its own150);

the accumulation of retinol-binding proteins (21 kDa in

size) may influence the ratio of TReg cells to TH17 cells; and

elevated levels of cytokines (typically 10–40 kDa in size)

contribute to systemic inflammation (FIG.4).

In proteinuria, proteins larger than 50 kDa in size

are excreted in the urine. The loss of immunoglobulins,

complement factors, zinc-binding protein and trans-

ferrin contributes to the acquired humoral and cel-

lular immunodeficient state that predisposes patients

with nephrotic syndrome to bacterial infections (FIG.4).

Furthermore, several functional Tcell and macrophage

defects have been described in these patients143 but their

functional relevance is unclear.

Kidney-derived hormones and hypertension.

VitaminD is activated by hydroxylation in the kidneys,

and declining levels in CKD lead to renal osteopathy.

VitaminD has immunosuppressive properties and low

levels predispose individuals to rheumatic disorders151.

These disorders are indeed more prevalent in CKD,

but it is unclear whether this is because low vitaminD

levels are pathogenic or because rheumatic diseases

cause CKD, or both. In addition, diseased kidneys

cannot produce sufficient quantities of erythropoietin,

resulting in the development of renal anaemia, which

contributes to oxidative stress that is induced by the

accumulation of uraemic toxins152; this is especially

common when anaemia is treated with iron, which

itself causes oxidativestress.

Blood levels of the blood pressure regulator renin are

increased in CKD as a result of the hypoperfusion of the

damaged nephrons (FIG.4). DCs express receptors for the

downstream mediator of renin, aldosterone, and respond

to aldosterone by promoting TH17 cell polarization153.

Aldosterone increases sodium reabsorption, and high

salt concentrations have recently been shown to maintain

TH17 cell polarization and to aggravate TH17 cell-driven

autoimmunity in mice154,155. IL-17 in turn increases

blood pressure by promoting vascular inflammation156.

Sodium retention also causes macrophages to produce

vascular endothelial growth factorC (VEGFC), which

induces neo-lymphangiogenesis in the skin to store the

salt157. This in turn increases extracellular volume and,

thus, blood pressure. Hypertension generally promotes

tissue inflammation, and tubulointerstitial nephritis is

known to raise blood pressure158. In summary, there are

complex feedback loops involving renin–angiotensin–

aldosterone stimulation, salt homeostasis, TH17 cells and

mononuclear phagocytes that may exacerbate hyperten-

sion and systemic inflammation, and that may promote

autoimmunity (FIG.4). The clinical implications of these

interactions warrant further studies.

Concluding remarks

Numerous discoveries have recently been made in the

field of renal immunology, which have clarified severe

and previously inexplicable kidney diseases; for exam-

ple, the identification of kidney-specific DAMPs, such

as uromodulin, that can drive sterile kidney inflam-

mation, or the identification of autoantigens that are

targeted in prevalent forms of glomerulonephritis, such

as PLA2R in membranous nephropathy. Knowledge

about relevant autoantigens is instrumental for the

design of non-invasive diagnostic procedures, such as

autoantibody assays. Progress has also been made in

understanding why the kidneys are frequent targets of

systemic autoimmunity, especially to injury by altered

antibodies, immune complexes and complement fac-

tors, and this has helped in implementing new treat-

ments in some cases. There are also anatomical and

physiological features that render the kidneys suscep-

tible to distinct forms of immune-mediated injury,

such as the high osmolarity of the renal medulla, which

favours crystal precipitation and inflammasome acti-

vation, or the constitutive renal protein catabolism of

tubular epithelial cells, which exposes them to Tcell

effector functions. Cellular immunity seems to require

more time to destroy the kidneys than it does to destroy

other tissues, making this organ a good site for basic

studies on immune cell crosstalk because immune cell

infiltrates can be observed over a longer time span.

Endotoxin tolerance

A transient state of

hyporesponsiveness of

the host or of cultured

macrophages and/or

monocytes to

lipopolysaccharide (LPS)

following previous exposure

to LPS.

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IMMUNOLOGY ADVANCE ONLINE PUBLICATION

Novel immune mechanisms that have been uncovered

during such studies — some of which are discussed in

this Review — may be relevant in the context of other

organ diseases. The revelation that the kidneys contrib-

ute to immune tolerance and that their detoxifying and

electrolyte-balancing activities ensure normal immune

effector cell function and intestinal microbial homeo-

stasis has been surprising. The kidney is the archetypal

organ of homeostasis and it is interesting to see that

this role now extends to the immunesystem.

Despite the progress that has been made, many

questions remain unanswered, some of which are

highlighted in this Review. Although the mechanisms

of kidney disease progression are increasingly well

understood, the factors that initiate these diseases often

remain unclear, for example, in IgA nephropathy, cres-

centic glomerulonephritis and membranous nephropa-

thy. However, the development of new therapies from

basic discoveries has already begun to affect clinical

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Acknowledgements

We apologize to all colleagues whose work could not be cited

or discussed in greater detail due to space restrictions. The

authors are supported by the German Research foundation

(DFG Klinische Forschergruppe 228, SFB704 and TR57,

Graduiertenkolleg 1202 and Excellence Cluster

ImmunoSensation) and the EU Consortia INTRICATE and

REDDSTAR.

Competing interests statement

The authors declare no competing financial interests.

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Supplementary information S1 (table) | Animal models of immune-mediated kidney disease

Experimental model /

human disease correlate

Establishment of the model, relevant pub-

lications

Features/ Advantages Limitations

Nephrotoxic nephritis

(NTN)/

Human crescentic glomeru-

lonephritis (GN)

NTN is induced by the injection of sheep / rab-

bit antiserum raised against glomerular basement

membrane components1-11

• Necrotizing and crescentic GN

• Heavy proteinuria

• Inducible in C57BL/6 mice

• GenerationofNTNserumisdifcult

• Dependent on genetic background

• Mouse anti-sheep Ig after 7-10d à transi-

tion to immune-complex GN

Accelerated nephrotoxic

nephritis/

Human immune-complex

Vaccination against IgG from the species in

which nephrotoxic serum was raised. Subsequent

injection of sub-nephritic antiserum dose creates

antibody sandwich in glomeruli that engages

complement and Fc receptors12-16

• Strong proteinuria and progressive

scarring

• Inducible in C57BL/6 mice

• As above plus:

• Different protocols for NTN induction

hinders result comparison

Experimental autoimmune

GN (EAG) /

Human anti-GBM nephritis

Induced by repetitive immunization with recom-

binant human/mouse alpha3(IV)NC1 collagen17-23

• Autologous model (animal´s own im-

mune response to the antigen)

• Inducible in mice and rats

• C57BL/6mice develop minor lesions,

(DBA/1 mice are more susceptible)

• Long duration

• Complicated antigen preparation proto-

col

MPO-induced GN /

Human pauci-immune focal

necrotizing glomerulonephri-

tis (piFNGN)

MPO knockout mice are immunized with mouse

MPO. Splenocytes from these mice are injected

intravenously into Rag2-/- mice24

• Necrotizing and crescentic GN, sys-

temic necrotizing vasculitis, includ-

ing necrotizing arteritis and hemor-

rhagic pulmonary capillaritis

• Verysophisticated,articialandnotwell

standardizedmodel(severalmodication

have been used)

• Mild disease unless co-stimulation with

LPS or anti-GBM antibodies

LAMP-2-induced GN/ Hu-

man pauci-immune focal ne-

crotizing glomerulo-nephritis

(piFNGN)

Passive model: Injecting WKY rats with IgG

specicforLAMP-2luminaldomain

Active model: immunization with LAMP-2 or its

molecular mimic, the bacterial adhesin FimH25

• Necrotizing and crescentic GN

• Systemic vasculitis

• Only tested in WKY rats that are highly

susceptible to FNGN

• Clinically relevant but needs further con-

rmation

Lupus-like IC-GN /

Human lupus nephritis

Spontaneous IC-GN developing from lupus-like

systemic autoimmunity in certain mouse strains

(NZB/NZW F1, MRL/lpr/lpr) leading to diffuse-

proliferative IC-GN7, 26-30

• Well characterized model • Modeldependsonthespecicgenetic

background

• Complicated crossbreeding procedure à

long duration

(Passive) Heymann nephritis

(HN) /

Human membranous ne-

phropathy

Injecting rats with a sheep antibody raised against

rat tubular brush border, resulting in formation of

subepithelial immune deposits and proteinuria31-35

• Well characterized model

• Time course for disease onset and

progression is short

• Inducible in several rats strains

• Not inducible in mice

• Target antigen (Megalin) is not expressed

in human podocytes

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Bacterial pyelonephritis /

Human bacterial pyelone-

phritis

Two subsequent transuretheral inoculations of

uropathogenic E. coli into the urinary bladder36-38

• Reliable mimic of human disease

including disease persistence and

relapses

• Fast model

• Complicated growth protocol for the

UPEC, work-intensive, timing of proce-

dure steps is critical

Unilateral ureteral obstruc-

tion (UUO) /

Human obstructive uropathy;

kidneybrosis

Surgical obstruction of one ureter to cause ob-

structive nephropathy. Glomerular compartment

remains unaffected39-46

• Easy, reliable, and fast (10 days)

• Standard screening model of renal

brogenesis

• Works in any species

• No functional outcome parameters as the

contralateralkidneyissufcienttomain-

tain renal excretory function

5/6 nephrectomy /

Advanced CKD

Surgical ablation of renal mass induces uraemia47,

• suitable to study the impact of CKD

on other systems

• species and strain-independent

• Major surgery required

• Few kidney tissue left for analysis

Adriamycin-nephropathy /

Human focal segmental

glomerulosclerosis

Injection of adriamycin causes toxic podocyte

injurythatprogressestointerstitialbrosis49, 50

• Reliable model of massive proteinu-

ria and focal-segmental glomerulo-

sclerosis

• Depends on precise dosing

• Only inducible in Balb/c, SCID, SV129

mice

Post-ischemic kidney injury/

Human acute kidney injury

including delayed graft func-

tion after kidney transplanta-

tion

Unilateral renal pedicle clamping induces tubular

necrosisandtransientsterileinammation.Long-

erischemiacausesprogressivebrosis.Bilateral

clamping causes uraemia and eventually uremic

death (depending on ischemia time)51-56

• Standard model of transient sterile

kidneyinammationfollowedby

epithelial repair.

• Relevant for kidney transplant injury

• Allows studying the resolution of

inammation

• Works in any strain and species

• dependent on temperature control during

anesthesia

Toxic acute kidney injury /

Human toxic acute kidney

injury

Cisplatin, folate or aristocholic injections cause

AKI by inducing bilateral tubular injury52

• Modeloftransientsterileinamma-

tion

• Works in any strain or species

• Compounds commercially available

at low cost

•

Septic acute kidney injury /

Human septic kidney injury

Systemic injection of LPS induces mild form of

AKI that mimics septic AKI51, 57

• Simple model

• Works in any strain or species

• Mild model, sensitive acute kidney in-

jury markers to detect injury

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Abatacept Decreases Renal T-cell Infiltration and Renal Inflammation and Ameliorates Progressive Renal Injury in Obese Dahl Salt-sensitive Rats Before Puberty

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Mar 2024

Prepubertal obesity (PPO) is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SS LepR mutant) rats was associated with increased T-cell infiltration and activation prior to puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SS LepR mutant rats before puberty. Four-week-old SS and SS LepR mutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T-cells by almost 50% in SS LepR mutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha (MIP-3α) while increasing IL-4 in SS LepR mutant rats without affecting SS rats. While not having an impact on blood glucose, abatacept reduced hyperinsulinemia and plasma triglycerides in SS LepR mutant rats without affecting SS rats. We did not observe any differences in MAP among the groups. Proteinuria was markedly higher in SS LepR mutant rats versus SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SS LepR mutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SS LepR mutant rats vs SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SS LepR mutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with PPO.

Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis

Article

Full-text available

Jun 2024
Hum Genom

Background Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. Methods In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. Results Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD. Conclusions In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.

Review of clinical characteristics and mortality outcomes in patients on maintenance hemodialysis during the Omicron surge: a single center experience

Article

Full-text available

Jun 2024
BMC PUBLIC HEALTH

Background This hemodialysis center experienced the pandemic from December 2022 to January 2023. Therefore, we sought to describe the clinical characteristics and mortality outcomes in hemodialysis patients during this Omicron surge. Methods According to whether they are infected, they are divided into two groups: SARS-CoV-2-positive and SARS-CoV-2-negative. The SARS-CoV-2-positive group was divided into a survival group and a non-survival group for comparison. Results 366 of 457 hemodialysis patients were infected with SARS-CoV-2. The most common symptoms observed were fever (43.2%) and cough (29.8%), Followed by diarrhea (1.4%). Hemodialysis patients with hypertension were more susceptible to SARS-CoV-2 infection. The lymphocyte count, serum creatinine, serum potassium, and serum phosphorus in the SARS-CoV-2-positive group were significantly lower than those in the SARS-CoV-2-negative group. The all-cause mortality rate for infection with SARS-CoV-2 was 5.2%. Only 7 of 366 SARS-CoV-2-positive patients were admitted to the intensive care unit, but 6 of them died. Intensive care unit hospitalization rates were significantly higher in the non-survival group compared with the survival group. White blood cells count, neutrophil count, C-reactive protein, AST, and D-dimer in the non-survival group were higher than those in the survival group. The lymphocyte count, hemoglobin concentration, serum creatinine, serum albumin, serum phosphorus and parathyroid hormone in the non-survival group were lower than those in the survival group. Age > 65 years, elevated C-reactive protein and AST are independent risk factors for death. Finally, no significant difference in vaccination status was found between the SARS-CoV-2-positive group and the negative group. Conclusions Hemodialysis patients are at high risk for SARS-CoV-2 infection. Ensuring the adequacy of hemodialysis treatment and maintaining good physical condition of patients are the top priorities.

Association of the Controlling Nutritional Status (CONUT) score with all-cause and cause-specific mortality in patients with diabetic kidney disease: evidence from the NHANES 2009–2018

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Full-text available

Apr 2024

Objective To investigate the association between the Controlling Nutritional Status (CONUT) score and all-cause and cause-specific mortality in patients with diabetic kidney disease (DKD). Design A retrospective cohort study. Setting and participants Data on patients with DKD from the National Health and Nutrition Examination Survey 2009–2018. Primary and secondary outcome measures All-cause mortality, cardiovascular disease (CVD)-related mortality, diabetes-related mortality and nephropathy-related mortality. Results A total of 1714 patients were included, with 1119 (65.29%) in normal nutrition group (a score of 0–1), 553 (32.26%) in mild malnutrition group (a score of 2–4) and 42 (2.45%) in moderate and severe malnutrition group (a score of 5–12), according to the CONUT score. After controlling for age, race, marital status, smoking, hypertension, CVD, diabetic retinopathy, poverty income ratio, antidiabetics, diuretics, urinary albumin to creatinine ratio, uric acid, energy, protein, total fat, sodium and estimated glomerular filtration rate, a higher CONUT score was associated with a significantly greater risk of all-cause death (HR 1.30, 95% CI 1.15 to 1.46, p<0.001). In contrast to patients with a CONUT score of 0–1, those who scored 5–12 had significantly increased risks of all-cause death (HR 2.80, 95% CI 1.42 to 5.51, p=0.003), diabetes-related death (HR 1.78, 95% CI 1.02 to 3.11, p=0.041) and nephropathy-related death (HR 1.84, 95% CI 1.04 to 3.24, p=0.036). Conclusion Moderate and severe malnutrition was associated with greater risks of all-cause death, diabetes-related death and nephropathy-related death than normal nutritional status in DKD. Close monitoring of immuno-nutritional status in patients with DKD may help prognosis management and improvement.

Not an immune cell, but they may act like one-cells with immune properties outside the immune system

Article

Apr 2024
IMMUNOL CELL BIOL

The cells presented in this work are not classified as cells that make up the immune system. They, however, present functions and molecules, which are characteristic of immune cells. These characteristic functions are, for example, sensing threat, performing phagocytosis, presentation of foreign antigens, cytokine release or enhancing immune memory. The enlisted immune response mechanisms are carried out by the possession of molecules such as Toll‐like receptors, receptors for the Fc fragment of IgG, major histocompatibility complex class II molecules, costimulatory CD80/CD86 proteins and molecules needed for NLRP3 (NOD‐like family pyrin domain containing 3) inflammasome activation. Thanks to these properties, the described nonimmune cells play an important role in the local immune response and support of the entire body in the fight against pathogens. They constitute the first line of defense of tissues and organs against pathogens and molecules recognized as harmful. The cells described in this article are particularly important in immunologically privileged places (e.g. the Bowman's capsule in the kidney), where “typical” immune cells normally do not have access. In this paper, we present immune‐like functions and molecule suites of resident kidney cells (podocytes and mesangial cells), cochlear resident cells, fibrocytes and fibroblasts, as well as some stem cells (mesenchymal stem cells and umbilical cord Wharton's jelly–derived cells).

IL-22, a vital cytokine in autoimmune diseases

Article

Full-text available

Apr 2024

Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.

Immunological aspects of chronic kidney disease diagnosed in adult patients

Article

Full-text available

Apr 2024

The purpose of the study was to study the immune status of patients diagnosed with SBK, to develop immunological diagnostic and prognostic criteria. It was found that SD3+- and SD4+-lymphocytes decreased by 1.43 and 1.07 times, SD8+-lymphocytes increased by 1.25 times, and IRI decreased by 1.32 times (T-immunodeficiency). SD25+ lymphocytes increased by 1.80 and 1.59 times, and SD95+ lymphocytes increased by 1.28 and 1.13 times in the blood of these patients. It was found that the amount of SD16+-lymphocytes was reliably increased compared to the parameters of healthy individuals. An imbalance was observed in the concentration of immunoglobulins in blood serum, while IL-4 increased by 11.84 times in patients, IL-6 was reliably reduced by 1.46 times compared to healthy people. Dynamic determination of serum concentrations of IL-4 and IL-6 was recommended as diagnostic and prognostic criteria for patients diagnosed with SBK.

No Evidence of Causal Effects between Renal Impairment and Muscle Wasting: a Two-Sample Mendelian Randomization Study

Preprint

Full-text available

Mar 2024

Background Numerous investigations have explored the potential correlation between renal impairment and muscle loss. However, the establishment of a definitive cause-and-effect relationship between these two remains elusive. Methods We utilized genome-wide association studies summary data from the CKDGen Consortium to identify genetically predicted estimated Glomerular Filtration Rate (eGFR), chronic kidney disease (CKD), and blood urea nitrogen (BUN) involving 567,460, 480,698, and 234,029 participants, respectively. To evaluate site-specific genetically predicted muscle mass, data from the UK Biobank were employed (n ≤ 454,835). The primary analysis relied on the inverse-variance weighted (IVW) method, with additional sensitivity analyses performed to validate the robustness of the MR results. Results No significant evidence could support that genetically predicted CKD was associated with appendicular and trunk muscle wasting [right leg FFM: IVW odds ratio (OR) = 1.010, confidence interval (CI) = 0.989 to 1.032, P-value = 0.355; left leg FFM: IVW OR = 1.009, CI = 0.988 to 1.031, P-value = 0.381; right arm FFM: IVW OR = 1.012, CI = 0.992 to 1.033, P-value = 0.231; left arm FFM: IVW OR = 1.010, CI = 0.990 to 1.030, P-value = 0.320; trunk FFM: IVW OR = 1.012, CI = 0.991 to 1.033, P-value = 0.279]. Similar estimations could also be observed in MR analyses of eGFR and BUN on muscle mass. Conclusions It is unlikely that genetically predicted renal impairment can causally increase the risk of muscle wasting. Clinically observed associations in epidemiologic studies might be attributed to metabolic homeostasis imbalances stemming from renal impairment.

Oleanolic acid and its analogues: promising therapeutics for kidney disease

Article

Full-text available

May 2024
Chin Med

Kidney diseases pose a significant threat to human health due to their high prevalence and mortality rates. Worryingly, the clinical use of drugs for kidney diseases is associated with more side effects, so more effective and safer treatments are urgently needed. Oleanolic acid (OA) is a common pentacyclic triterpenoid that is widely available in nature and has been shown to have protective effects in kidney disease. However, comprehensive studies on its role in kidney diseases are still lacking. Therefore, this article first explores the botanical sources, pharmacokinetics, derivatives, and safety of OA, followed by a summary of the anti-inflammatory, immunomodulatory, anti-oxidative stress, autophagy-enhancing, and antifibrotic effects of OA and its analogues in renal diseases, and an analysis of the molecular mechanisms, aiming to provide further insights for the development of novel drugs for the treatment of kidney diseases.

Artificial intelligence identifies spatial fingerprints of kidney-resident macrophages and brain microglia

Preprint

Full-text available

Apr 2024

The isolation of immune cells from tissues for single cell RNA sequencing (scRNA-seq) loses spatial information. Here we employed machine learning methods to identify transcriptomic fingerprints containing such information. We used murine kidney and brain as organs with macroscopically distinguishable regions and generated separate scRNA-seq datasets of immune cells from distinct areas. Several machine learning algorithms were utilized to identify highly variable genes harboring spatial information. Multilayer perceptron (MLP) performed best at predicting the position of kidney-resident macrophages with an accuracy of >75%. No algorithm allowed predicting the position of motile immune cells like monocyte-derived macrophages or lymphocytes. Also kidney dendritic cell positions were not predictable, presumably because these were found to mostly belong to a recently described subset with monocyte lineage (DC3). The macrophage spatial fingerprints were enriched in pathways involved in microenvironmental responses and cellular adaptation, and they showed a gender bias. In an experimental crescentic glomerulonephritis, macrophage positioning was predicted with an accuracy of 69-71%. Also in a human dataset, our algorithm operated with comparable efficiency. Applying our strategy to brain datasets predicted microglia positions with 74% accuracy. Our approach to predict the location of tissue-resident macrophages may be applicable to organs other than kidney and brain.

Deciphering the transcriptional network of the dendritic cell lineage

Article

Full-text available

Sep 2012

Exclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression

Article

Full-text available

Sep 2013
J CLIN INVEST

DCs and macrophages both express the chemokine receptor CX3CR1. Here we demonstrate that its ligand, CX3CL1, is highly expressed in the murine kidney and intestine. CX3CR1 deficiency markedly reduced DC numbers in the healthy and inflamed kidney cortex, and to a lesser degree in the kidney medulla and intestine, but not in other organs. CX3CR1 also promoted influx of DC precursors in crescentic glomerulonephritis, a DC-dependent aggressive type of nephritis. Disease severity was strongly attenuated in CX3CR1-deficient mice. Primarily CX3CR1-dependent DCs in the kidney cortex processed antigen for the intrarenal stimulation of T helper cells, a function important for glomerulonephritis progression. In contrast, medullary DCs played a specialized role in inducing innate immunity against bacterial pyelonephritis by recruiting neutrophils through rapid chemokine production. CX3CR1 deficiency had little effect on the immune defense against pyelonephritis, as medullary DCs were less CX3CR1 dependent than cortical DCs and because recruited neutrophils produced chemokines to compensate for the DC paucity. These findings demonstrate that cortical and medullary DCs play specialized roles in their respective kidney compartments. We identify CX3CR1 as a potential therapeutic target in glomerulonephritis that may involve fewer adverse side effects, such as impaired anti-infectious defense or compromised DC functions in other organs.

Distinct Genetic Subsets in ANCA-Associated Vasculitis

Article

Oct 2012

HB-EGF promotes immune glomerular injury and renal failure in crescentic rapidly progressive glomerulonephritis through activation of the epidermal growth factor receptor

Article

Jun 2007

U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7 (vol 107, pg 3229, 2006)

Article

May 2006

Savarese

Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation

Article

Mar 2011

B. McDonald

The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited

Article

Feb 2004

J J Weening

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving ≥50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Genetic Tracing via DNGR-1 Expression History Defines Dendritic Cells as a Hematopoietic Lineage

Article

Aug 2013

Mononuclear phagocytes are classified as macrophages or dendritic cells (DCs) based on cell morphology, phenotype, or select functional properties. However, these attributes are not absolute and often overlap, leading to difficulties in cell-type identification. To circumvent this issue, we describe a mouse model to define DCs based on their ontogenetic descendence from a committed precursor. We show that precursors of mouse conventional DCs, but not other leukocytes, are marked by expression of DNGR-1. Genetic tracing of DNGR-1 expression history specifically marks cells traditionally ascribed to the DC lineage, and this restriction is maintained after inflammation. Notably, in some tissues, cells previously thought to be monocytes/macrophages are in fact descendants from DC precursors. These studies provide an in vivo model for fate mapping of DCs, distinguishing them from other leukocyte lineages, and thus help to unravel the functional complexity of the mononuclear phagocyte system.

Immunoregulation in Urinary Tract Inflammation--A Role of Tamm-Horsfall Glycoprotein: Tamm-Horsfall Glycoprotein Links Innate Immune Cell Activation with Adaptive Immunity via a Toll-Like Receptor4Dependent Mechanism. J Clin Invest 115: 468-475, 2005

Article

Feb 2005

Marcus D Saemann

Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1. Rapid Communication

Article

Aug 1999

Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1.Background Fractalkine is a newly identified T-cell and monocyte/macrophage (Mφ) chemokine with a transmembrane domain and is a cell-surface protein on activated endothelium. It can mediate adhesion of cells expressing the fractalkine receptor CX3CR1. These unique features make fractalkine well suited for leukocyte recruitment in tissues with high blood flow as in the renal glomerulus.Methods Fractalkine expression in glomeruli and response of isolated glomerular inflammatory cells to fractalkine were studied in the Wistar-Kyoto (WKY) crescentic glomerulonephritis model. Antibody was used to confirm the proinflammatory role of fractalkine.ResultsFractalkine was markedly induced in the endothelium of nephritic rat glomeruli, and inflammatory leukocytes infiltrating the glomeruli expressed increased levels of CX3CR1. Anti-CX3CR1 antibody treatment dramatically blocked leukocyte infiltration in the glomeruli, prevented crescent formation, and improved renal function.Conclusions Fractalkine plays a central role in leukocyte trafficking at the endothelium in the high-flow glomerular circuit and, in turn, implicates CX3CR1 as a prime drug target for therapeutic intervention of endothelium-related inflammatory diseases.

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

Abstract

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