F1000Research 2015, 4(F1000 Faculty Rev):1212 Last updated: 12 FEB 2016

REVIEW
Recent advances in understanding of chronic kidney disease
[version 1; referees: 3 approved]
Junna Yamaguchi, Tetsuhiro Tanaka, Masaomi Nangaku
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, 113-0033, Japan

First published: 04 Nov 2015, 4(F1000 Faculty Rev):1212 (doi: Open Peer Review
v1 10.12688/f1000research.6970.1)
Latest published: 04 Nov 2015, 4(F1000 Faculty Rev):1212 (doi:
10.12688/f1000research.6970.1) Referee Status:

Abstract Invited Referees

Chronic kidney disease (CKD) is defined as any condition that causes reduced 1 2 3
kidney function over a period of time. Fibrosis, tubular atrophy and interstitial
inflammation are the hallmark of pathological features in CKD. Regardless of
version 1
initial insult, CKD has some common pathways leading CKD to end-stage published
kidney disease, including hypoxia in the tubulointerstitium and proteinuria. 04 Nov 2015
Recent advances in genome editing technologies and stem cell research give
great insights to understand the pathogenesis of CKD, including identifications
of the origins of renal myofibroblasts and tubular epithelial cells upon injury. F1000 Faculty Reviews are commissioned
Environmental factors such as hypoxia, oxidative stress, and epigenetic factors from members of the prestigious F1000
in relation to CKD are also discussed. Faculty. In order to make these reviews as
comprehensive and accessible as possible,
peer review takes place before publication; the
This article is included in the F1000 Faculty referees are listed below, but their reports are
Reviews channel. not formally published.

1 Motoko Yanagita, Graduate School of

Medicine and Faculty of Medicine Kyoto
University Japan

2 William Couser, University of Washington

USA

3 Takashi Yokoo, Jikei University School of

Medicine Japan

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 F1000Research 2015, 4(F1000 Faculty Rev):1212 Last updated: 12 FEB 2016

Corresponding author: Masaomi Nangaku ([email protected])

How to cite this article: Yamaguchi J, Tanaka T and Nangaku M. Recent advances in understanding of chronic kidney disease [version 1;
referees: 3 approved] F1000Research 2015, 4(F1000 Faculty Rev):1212 (doi: 10.12688/f1000research.6970.1)
Copyright: © 2015 Yamaguchi J et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Grant information: The work of the authors is supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan (26111003 to MN) and Grants-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science (15H04835 to MN and 26461215 to TT).
Competing interests: The authors declare that they have no competing interests.
First published: 04 Nov 2015, 4(F1000 Faculty Rev):1212 (doi: 10.12688/f1000research.6970.1)

F1000Research
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 F1000Research 2015, 4(F1000 Faculty Rev):1212 Last updated: 12 FEB 2016

Introduction Kidney development and regeneration

Chronic kidney disease (CKD) is a growing health burden with an Nephrogenesis and nephron number
increasing incidence and prevalence worldwide. An estimated 13% Nephrogenesis requires precise sequential and reciprocal interac-
of adults in the US and Japan have CKD, and the proportion of tions between renal progenitor cells and their integration with vas-
affected individuals increases each year because of an aging popu- culature. In mammals, the metanephric kidney develops through
lation and increases in diabetes and hypertension, the most com- interactions between the metanephric mesenchyme (MM) and uretic
mon causes of CKD1,2. CKD is a risk factor for end-stage kidney bud10. MM nephron progenitors give rise to Six2+ cap mesenchyme
disease (ESKD), cardiovascular disease, and overall mortality3. In progenitor cells (which later differentiate into nephron epithelia,
the US, the economic costs of CKD and ESKD in patients over including proximal and distal tubular cells, the loop of Henle, and
age 65 are $60 billion, representing 24% of total Medicare expen- podocytes) and Foxd1+ cortical stromal progenitor cells (which later
ditures in 20114. Currently, the predominant problem is that thera- differentiate into cortical and medullary interstitial cells, mesangial
peutic options for CKD are limited and often ineffective, meaning cells, and pericytes)11–14. Nephrogenesis ceases at approximately
that there is essentially no cure for CKD. Therefore, translating the third post-natal day in mice15 and 36 weeks of gestation in
our understanding of CKD pathogenesis into treatments is a high humans16. Low nephron number is associated with a risk of renal
priority in the field. disease and hypertension17, and low birth weight and prematurity
are the most robust clinical surrogates for low nephron number18.
CKD is defined as any condition that causes abnormalities of kid- The molecular event that governs the end of nephron formation is
ney structure or function for a duration of more than 3 months with unknown and is an ongoing topic of research10,19. The regenerative
notable implications for patient health5,6 (Table 1). Regardless of capacity of glomeruli is limited after birth, and many studies have
initial etiology, fibrosis, tubular atrophy, and interstitial inflamma- focused on the source of regenerated tubular cells following acute
tion are common pathological features of CKD. Careful histologi- kidney injury (AKI) and the origin of myofibroblasts in CKD.
cal observations have demonstrated that functional impairment of
the kidney is more highly correlated with tubulointerstitial dam- Origin and regeneration of tubular cells
age than with glomerular injury, which is often associated with the A proliferative burst of tubular cells occurs during kidney injury.
loss of peritubular capillaries (PTCs)7. In addition, hypoxia is now Sophisticated lineage-tracing studies have excluded the possibil-
accepted to be the final common mechanism underlying the pro- ity of extrarenal cells contributing to tubular regeneration20. Recent
gression of CKD to ESKD, which we discuss later in this article8,9. studies further support the self-proliferation of existing differenti-
ated tubular cells rather than the contribution of stem-like cells to
The current understanding of CKD is based on a broad range of epithelial proliferation after AKI21–23.
studies focused on the genetic risk factors for the development and
progression of CKD, the pathogenesis of renal fibrosis (e.g., the Whereas the origin of the repairing tubule is becoming clearer, less
origin and activation of renal myofibroblasts, fibrogenic mediators is known regarding the signals that regulate epithelial dedifferentia-
and signaling, crosstalk with tubular cells, vasculature, and inflam- tion, proliferation, and polarization. One signal is known to derive
matory cells), tubular injury and repair, mediators and dynamics from inflammatory cells. Cellular stress in tubules induces the acti-
of renal inflammation, and cellular adaptations to the microenvi- vation of innate immunity through the production of cytokines and
ronment such as hypoxia and oxidative stress. This article reviews chemokines, which exacerbate tubular injury by recruiting mac-
some of the recent advances in our understanding of CKD from two rophages, neutrophils, and proinflammatory lymphocytes24. One
vantages: cellular regeneration and hypoxia. A better understand- study demonstrates that a lack of interleukin-1 receptor-associated
ing of CKD pathogenesis will hopefully provide insights leading to kinase-M leads to persistent proinflammatory macrophage infil-
better management of CKD in the future. tration with higher tubular phagocytosis activity and thus limited

Table 1. Definition of chronic kidney disease (KDIGO 2012).

Criteria for chronic Definition of criteria

kidney diseasea
One or more marker of Albuminuria (AER of ≧30 mg per 24 hours and ACR of ≧30 mg/g)
kidney damage Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by imaging
History of kidney transplantation
Decreased GFR GFR of less than 60 ml/min per 1.73 m2
a
Either of the criteria below should be present for more than 3 months. Data are from the KDIGO (Kidney
Disease: Improving Global Outcomes) 2012 Clinical Practice Guideline for the Evaluation and Management
of Chronic Kidney Disease. ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; GFR, glomerular
filtration rate.

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tubular re-epithelialization25. This effect was reversed by tumor Mediators of chronic kidney disease progression
necrosis factor-alpha blockade, indicating that cytokine-induced Proteinuria
tubular attack overwhelms tubular repair capacity. Advances in Proteinuria is an established mediator of CKD pathogenesis, and
genetic manipulation at the desired time point, together with a bet- lowering proteinuria retards CKD progression37–40. Protein overload
ter understanding of myofibroblasts, now allow the study of signal- exacerbates tubulointerstitial injury in a number of ways: direct
ing from fibroblasts or myofibroblasts to tubular cells in vivo. tubular injury, including lysosomal rupture and energy depletion;
activation of intratubular complement components, which leads to
However, whether tubular regenerative capacity is itself limited in tubular cell activation or injury; and stimulation of inflammatory
CKD is unknown. The intrinsic limit of tubular regenerative capac- and fibrogenic mediators41–43.
ity may be related to disturbances in metabolism, endoplasmic
reticulum stress, cell cycle arrest, or DNA damage26. In addition, the Hypoxia
first direct reprogramming of renal epithelial cells to Six2+ neph- The fact that nonproteinuric CKD is common and that renin-
ron progenitor cells was accomplished by the addition of a com- angiotensin-aldosterone inhibitors have renoprotective effects
bination of six transcription factors, including SIX2 and OSR127. beyond lowering blood pressure and reducing proteinuria suggests
These reprogrammed cells differentiated into epithelial cells in a that there are other key mediators of CKD pathogenesis. Chronic
re-aggregation assay, providing another strategy for replacing the hypoxia of the tubulointerstitium is now widely accepted as the
epithelial layer if correct integration into nephrons can be achieved. final common pathway in CKD progression8,9 (Figure 1). Once PTC
In parallel, several groups have succeeded in the induction of cells rarefaction occurs, hypoxia in the affected region triggers pheno-
of renal lineage, including intermediate mesoderm as well as indi- typic changes in tubular cells (e.g., proliferation rate and apoptosis),
vidual differentiated cells such as proximal tubular cells or podo- which in turn serve as a source of mediators involved in inflam-
cytes from embryonic stem or induced pluripotent stem cells11,28,29. matory cell infiltration and fibrosis. Fibrosis further impairs local
Similar to the maintenance of nephron progenitor potency in the oxygenation, while hypoxia induces sterile inflammation. Hypoxic
stromal-epithelial niche during kidney development, sophisticated responses are also induced by inflammatory transcription factors44.
programs may be required to maintain this potency30. Thus, hypoxia is intricately linked to inflammation and oxidative
stress, causing a vicious cycle leading to CKD pathogenesis.
Origin of myofibroblasts and their transdifferentiation
Myofibroblasts are extracellular matrix-producing cells that drive Hypoxia-inducible factors (HIFs) are transcription factors that
fibrogenesis. The origin of renal myofibroblasts has been another function as master regulators of biological adaptive responses to
area of major debate. Currently, FoxD1-Cre-labelled pericytes31, hypoxia45. HIFs consist of an alpha subunit (HIF-1α, HIF-2α, and
P0 (myelin protein 0)-Cre-labelled resident fibroblasts32, and renal HIF-3α) and a common beta subunit. Under normoxic conditions,
erythropoietin-producing (REP) cells33 are reported as the origins HIF-α is hydroxylated by prolyl hydroxylase (PHD) and undergoes
of myofibroblasts. The absence of permanent specific markers and a proteasomal degradation. HIFs regulate the expression of more than
shared developmental program makes it difficult to determine their 150 genes, including those involved in anaerobic metabolism (e.g.,
precise origin. Their similar localization—near CD31+ endothelial glucose transporter-1), hematopoiesis (erythropoietin, or EPO),
cells in the interstitium—and gene expression patterns (PDGFRβ and angiogenesis (e.g., VEGF and angiopoietins). In response to
(platelet derived growth factor receptor beta) and CD73) suggest hypoxia in kidney, HIF-1α is expressed in tubular cells, whereas
that they represent an overlapping cell population. A recent study HIF-2α is expressed mainly in endothelial cells and interstitial
reported that Gli1+PDGFRβ+CD73− cells, a small fraction of the fibroblasts46.
total PDGFRβ population, are the major cellular origin of myofi-
broblasts in multiple organs, including kidney, heart, and liver34. In kidney disease, despite the hypoxic milieu, HIF activation is
Unified theories require further investigation. considered to be suboptimal. In the early phase of UUO (day 2),
induction of HIF-1α and its target genes was disrupted, although
Triggers of the transdifferentiation of resident fibroblasts, REPs, pronounced hypoxia was confirmed by a hypoxia-detecting probe33.
or pericytes to alpha-smooth muscle actin-producing myofibrob- In another study using a rat CKD model, indoxyl sulphate, a repre-
lasts also remain unclear. Factors produced by injured tubular and sentative uremic toxin, impeded the recruitment of transcriptional
inflammatory cells, including vascular endothelial growth fac- coactivators to HIF-1α, causing insufficient upregulation of HIF-1
tors (VEGFs), platelet-derived growth factors (PDGFs), fibrob- target genes while leaving HIF-1α protein level unaffected47. This
last growth factors, and transforming growth factor-beta, activate was reversed by an oral adsorbent for CKD, AST-120, that is cur-
pericytes and induce their detachment from capillaries and their rently in clinical use. Indeed, genetic and pharmacological modu-
transdifferentiation to myofibroblasts33,35. In a typical inflammatory lation of HIFs in the kidney has been a subject of great interest,
fibrogenic model known as unilateral ureteric obstruction (UUO), not only for investigating the roles of HIFs but also as a potential
this transdifferentiation was found to be partially reversible in therapeutic tool. The renoprotective effects of HIF activation have
REPs after removal of the insult33. Recently, a comprehensive DNA been demonstrated in various AKI models, whereas those in CKD
microarray analysis of pericyte-to-myofibroblast transition was models have variable outcomes48. Pepck-Cre-mediated conditional
performed by using translational ribosome affinity purification in knockout of HIF-1α in proximal tubules ameliorated fibrosis in
UUO, which may yield clues to help characterize these cells36. UUO49, whereas global HIF activation by Vhl knockout ameliorated

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Figure 1. Pathogenesis of chronic kidney disease. Tubulointerstitial hypoxia, inflammation, and oxidative stress form a vicious cycle in
chronic kidney disease (CKD) progression. Glomerular injury results in a decrease in peritubular capillary (PTC) blood flow and subsequent
tubulointerstitial hypoxia. Hypoxia and proteinuria cause tubular injury, which in turn triggers the production of cytokines and chemokines
and promotes inflammatory cell infiltration into the tubulointerstitium. Damaged PTC also facilitates inflammatory cell infiltration. Hypoxia,
inflammation, and oxidative stress promote the transdifferentiation of resident fibroblasts, renal erythropoietin-producing cells, or pericytes to
extracellular matrix (ECM)-producing myofibroblasts. Direct interactions between the injured tubular cells and myofibroblasts also play a role.
Fibrosis further impairs local oxygenation.

inflammation and fibrosis in the same model50. Global HIF activa- lipopolysaccharide-treated mice via HIF-2 activation54. This find-
tion by PHD inhibition reduced the tubulointerstitial injury associ- ing is in accordance with the observation that the pharmacological
ated with reduced tubular injury and capillary rarefaction in CKD activation of HIFs by PHD inhibitors augmented EPO production in
rats51 and improved oxygen metabolism in diabetic rats52. HIF-1 patients with ESKD55. Notably, PHD2 knockout-mediated HIF acti-
in tubular cells exhibits both autocrine (e.g., cell cycle regulation vation in REPs did not affect the inflammatory or fibrotic pathology
and metabolic regulation) and paracrine (e.g., angiogenic and fibro- of UUO; REP plasticity seems to be regulated by multiple signals
genic factors) signaling, which may result in different long-term at multiple levels.
renal outcomes. Additional cell type-specific and time-dependent
manipulations of HIF activity may yield further insight for the What causes angiogenesis insufficiency in CKD? Hypoxia signals
development of future kidney therapies. generally promote angiogenesis56, and PTC development is thought
to be regulated by angiogenic factors (e.g., VEGF, fibroblast growth
Renal anemia is a frequent complication of CKD. The pathogene- factors, angiopoietins, and PDGF) secreted from tubular cells as
sis of renal anemia includes chronic inflammation, iron deficiency, well as endothelial and mesenchymal precursors. Doxycycline-
shortened erythrocyte half-life, and, most importantly, EPO defi- regulated tubular-specific VEGF-A deletion during development
ciency. One explanation for the observed EPO deficiency is the led to a marked reduction of PTC, whereas deletion of VEGF-A
accumulated indoxyl sulphate observed in CKD. Indoxyl sulphate is post-natally between days 21 and 42 did not result in pronounced
reported to suppress EPO production in a HIF-dependent manner53. PTC rarefaction57. This suggests a difference in tubulovascular cross-
The identification of REPs also provided insight into the causes of talk in the developing and adult kidney. Another study that focused
EPO deficiency. REPs were repressed of EPO producing potential on pericyte-endothelial crosstalk in the adult kidney58 showed that
upon transdifferentiation to myofibroblasts in UUO through the acti- PDGFβ and VEGF receptor signaling induced pericyte detach-
vation of nuclear factor-kappa-B (NF-κB) signals33. REP-specific ment from PTC and their transdifferentiation to myofibroblasts in
PHD2 knockout mice recovered EPO production in UUO and UUO. These unusual behaviors by angiogenic factors may in part

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explain the insufficient angiogenesis in adult kidneys, including Epigenetics

CKD kidneys. Epigenetic regulation in CKD is emerging as an important topic. As
proposed in the “metabolic memory” theory of diabetic nephropa-
Oxidative stress thy, hypoxia may be remembered via epigenetic changes to play a
Oxidative stress, another type of oxygen disturbance, is inevitably crucial role in the pathogenesis of CKD. Epigenetic modifications
present in CKD and inseparably linked to hypoxia and inflammation59 include cytosine DNA methylation, noncoding RNA, and histone
(Figure 1). Oxidative stress is caused by increased reactive oxy- post-translational modification73. Differentially methylated regions
gen species (ROS) production or impaired antioxidant capacity, were observed in the cortical tubules of CKD patients and controls,
or both. Factors such as proteinuria, uremic toxin, hyperglyc- especially in enhancer regions of key fibrotic genes74. Microar-
emia, and increased activity in the intra-renal angiotensin system ray approaches have identified a number of potential microRNAs
contribute to increased oxidative stress in CKD. The Keap1-Nrf2 responsive in CKD animal models75. MicroRNA-21 was shown to
(Kelch-like ECH-associated protein 1-nuclear factor-erythroid- promote fibrosis by repressing peroxisome proliferator-activated
2-related factor 2) system is the major regulator of cytoprotective receptor-alpha, by either germline deletion of miR21 or oligonu-
responses to endogenous and exogenous stresses caused by ROS. cleotide administration of anti-miR21 in UUO76. Hypoxia is also
Impaired Nrf2 activity is observed in various animal CKD models, reported to alter the chromatin conformational structure dynami-
and the activation of Nrf2 ameliorates antioxidant defense and inflam- cally and cause histone modifications in human umbilical vein
mation. Pharmacological activation of the Nrf2 pathway has been endothelial cells, which result in transcriptional changes of HIF-1
challenged with synthetic triterpenoid bardoxolone methyl in type target genes77. Prolonged ischemic-reperfusion injury has caused
2 diabetic CKD patients. A phase 2 BEAM (52-Week Bardoxolone histone modifications at proinflammatory and profibrotic genes prior
Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial to fibrosis, which may be related to CKD pathogenesis78. Interven-
showed promise for the use of bardoxolone methyl to increase esti- tional studies for these epigenetic modifications are anticipated.
mated glomerular filtration rate (eGFR) compared with a placebo
(mean change of 8.2 to 11.4 ml/min per 1.73 m2, depending on the Perspectives
dose group) in moderate-to-severe diabetic CKD patients60 (eGFR Technological developments in genome editing, genome-wide
20 to 45 ml/min per 1.73 m2). Notably, increased albuminuria was analysis, and dynamic multiplex four-dimensional measurement, as
observed in the bardoxolone methyl group, despite significantly well as advances in the fields of stem cell and regenerative biology
improved kidney function. A study in cynomolgus monkeys sug- are considerable. It is now possible to investigate the contextual,
gests that bardoxolone methyl decreases the expression of megalin, environmental, and interdependent coordination between multi-
which is primarily responsible for albumin reabsorption in proxi- ple players in the kidney79. Needless to say, translating the results
mal tubules, resulting in increased albuminuria61. Whether and how of basic research in animal models to the bedside will require a
Nrf2 is related to reduced megalin expression remain unknown. The number of additional studies. One example is the lack of animal
subsequent phase 3 BEACON (Bardoxolone Methyl Evaluation in models that mimic human CKD pathophysiology. To overcome
Patients with Chronic Kidney Disease and Type 2 Diabetes Melli- these issues, research using samples from patients with CKD is
tus: the Occurrence of Renal Events) trial in diabetic CKD stage 4 under way. Overall, this is an exciting time for CKD research, as
patients (eGFR of 15 to less than 30 ml/min per 1.73 m2) was termi- a fuller understanding of its pathogenesis lays the foundation for
nated because of a higher rate of cardiovascular events in the bar- pathogenesis-based kidney therapy.
doxolone methyl group than in the placebo group62. Controversies
exist as to the cause of increased cardiovascular events during bar- Abbreviations
doxolone methyl treatment and as to the appropriate selection of a AKI, acute kidney injury; CKD, chronic kidney disease; eGFR,
target patient population for this therapy63,64. Interventions designed estimated glomerular filtration rate; EPO, erythropoietin; ESKD,
to prevent oxidative stress remain important therapeutic options end-stage kidney disease; HIF, hypoxia-inducible factor; MM,
for CKD. metanephric mesenchyme; Nrf2, Nuclear factor-erythroid-2-related
factor 2; PDGF, platelet-derived growth factor; PDGFRβ, platelet-
New technology-driven advances in understanding derived growth factor receptor beta; PHD, prolyl hydroxylase;
of chronic kidney disease PTC, peritubular capillary; REP, renal erythropoietin-producing;
-Omics ROS, reactive oxygen species; TAL, thick ascending limb of the
‘-Omics’ approaches have rapidly expanded our understanding of loop of Henle; UUO, unilateral ureteric obstruction; VEGF, vascu-
CKD. Genome-wide association studies have identified multiple lar endothelial growth factor.
genetic loci associated with kidney function-related traits65–68. The
shared loci among multiple ethnic groups include the UMOD locus,
which encodes the abundant urinary protein uromodulin produced Competing interests
by the epithelial cells of the thick ascending limb of the loop of The authors declare that they have no competing interests.
Henle (TAL). Further animal studies have demonstrated the causal
role of UMOD risk variants in hypertension and CKD by modulating Grant information
salt handling in the TAL69. An example for a specific ethnic group The work of the authors is supported by a Grant-in-Aid for Scientific
is APOL1. The higher incidence of ESKD in African Americans Research on Innovative Areas from the Ministry of Education, Cul-
compared with European Americans led to the identification of ture, Sports, Science, and Technology of Japan (26111003 to MN)
APOL1 variants as risk factors for the development and progression and Grants-in-Aid for Scientific Research from the Japan Society for
of CKD among African Americans in the general population70–72. the Promotion of Science (15H04835 to MN and 26461215 to TT).

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Open Peer Review

Current Referee Status:

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a
service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees
provide input before publication and only the final, revised version is published. The referees who approved the
final version are listed with their names and affiliations but without their reports on earlier versions (any comments
will already have been addressed in the published version).

The referees who approved this article are:

Version 1

1 Takashi Yokoo, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, 105-8461,
Japan
Competing Interests: No competing interests were disclosed.

2 William Couser, University of Washington, Washington, USA

Competing Interests: No competing interests were disclosed.

3 Motoko Yanagita, Graduate School of Medicine and Faculty of Medicine Kyoto University, Kyoto, Japan
Competing Interests: No competing interests were disclosed.

F1000Research
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