Journal of Nephrology

https://doi.org/10.1007/s40620-020-00793-2

REVIEW

AKI: an increasingly recognized risk factor for CKD development

and progression
J. T. Kurzhagen1   · S. Dellepiane2   · V. Cantaluppi3   · H. Rabb1 

Received: 14 April 2020 / Accepted: 26 June 2020

© Italian Society of Nephrology 2020

Abstract
Acute kidney injury (AKI) is an increasing health burden with high morbidity and mortality rates worldwide. AKI is a risk
factor for chronic kidney disease (CKD) development and progression to end stage renal disease (ESRD). Rapid action is
required to find treatment options for AKI, plus to anticipate the development of CKD and other complications. Therefore,
it is essential to understand the pathophysiology of AKI to CKD transition. Over the last several years, research has revealed
maladaptive repair to be an interplay of cell death, endothelial dysfunction, tubular epithelial cell senescence, inflammatory
processes and more—terminating in fibrosis. Various pathological mechanisms have been discovered and reveal targets for
potential interventions. Furthermore, there have been clinical efforts measures for AKI prevention and progression including
the development of novel biomarkers and prediction models. In this review, we provide an overview of pathophysiological
mechanisms involved in kidney fibrosis. Furthermore, we discuss research gaps and promising therapeutic approaches for
AKI to CKD progression.

Keywords  AKI · CKD · AKD · Renal fibrosis · Mechanisms

Abbreviations bFGF Basic fibroblast growth factor

ADQI Acute disease quality initiative BM Bone marrow
Ag-presentation Antigen presentation BUN Blood urea nitrogen
AKD Acute kidney disease CCL2 CC-chemokine ligand 2
AKI Acute kidney injury CCR2 C–C chemokine receptor type 2
Akt Protein kinase B, PKB CDDO-dhTFEA CDDO-9,11-dihydro-trifluoroethyl
Alpha-SMA α-Smooth muscle actin Amide
AQP2 Aquaporine 2 CDDO-Im CDDO-imidazole
ASC Adipose mesenchymal stem cells CDDO-Me CDDO-methyl ester
ATN Acute tubular necrosis CI Confidence interval
BC-SC Blood cord stem cells CKD Chronic kidney disease
CRAC channel Ca2+ release-activated ­Ca2+ channel
CRRT​ Continuous renal replacement therapy
V. Cantaluppi: On behalf of the AKI and CRRT Project Group of
the Italian Society of Nephrology (SIN). CTGF CCN2 or connective tissue growth
factor
* H. Rabb Cxcl12 CXC-Motif-Chemokin 12
hrabb1@jhmi.edu CVD Cardiovascular diseases
1
Division of Nephrology, Johns Hopkins Hospital, Johns DAMPs Damaged-associated molecular
Hopkins University School of Medicine, Ross 965, 720 patterns
Rutland Ave, Baltimore, MD 21206, USA DCs Dendritic cells
2
Icahn School of Medicine at Mount Sinai, New York, NY, DGF Delayed graft function
USA DM Diabetes mellitus
3
Nephrology and Kidney Transplantation Unit, Department DN αβTCR double negative T cells
of Translational Medicine, University of Piemonte Orientale ECM Extracellular matrix
(UPO), “Maggiore Della Carità” University Hospital, EGF Epidermal growth factor
Novara, Italy

13
Vol.:(0123456789)

EMP Epithelial-mesenchymal plasticity
EMT Epithelial-mesenchymal transition
EndMT Endothelial-to-mesenchymal transition
EPC Endothelial progenitor cells
ER Endoplasmic reticulum
ERK 1/2 Extracellular-signal-regulated kinase
1/2
ESRD End stage renal disease
EVs Extracellular vesicles
FGF-2 Fibroblast growth factor
GFR Glomerular filtration rate
Glom Glomerular
HGF Hepatocyte growth factor
HPSE Heparanase
HR Hazard ratio
HSC Hematopoietic SC
IFN-γ Interferon γ
IGF1 Insulin-like growth factor 1
IGFBP7 Insulin-like growth factor-binding
protein 7
IL Interleukin
iPS Induced pluripotent SC
IRI Ischemic reperfusion injury
ISN International Society of Nephrology
KC Keratinocyte-derived chemokine
KDIGO Kidney disease improving global
outcomes
Keap1 Kelch-like ECH-associated protein 1
KIM-1 Kidney injury molecule-1
KO Knock out
LSC Liver stem cells
M2 M2 macrophages
MCP-1 Monocyte chemoattractant protein-1
MHC Major histocompatibility complex
MLKL Mixed lineage kinase domain-like
protein
MMP Matrix metalloprotease
MSC Mesenchymal stem cells
NET Neutrophil extracellular traps
NF-κB Nuclear factor ’kappa-light-chain-
enhancer’ of activated B-cells
NGAL Neutrophil gelatinase-associated
lipocalin
NK cells Natural killer cells
NO Nitric oxide
Nrf2 Nuclear factor erythroid 2-related fac-
tor 2
Orai1 Calcium release-activated calcium
channel protein 1
PDGF Platelet-derived growth factor
PIIINP Procollagen type III N-terminal peptide
PTEN Phosphatase and Tensin homolog
13
Journal of Nephrology
RANTES Regulated upon activation, normal
T-cell expressed and secreted
RIPK1 Receptor-interacting protein kinase-1
SC Stem cells
Snai1 Snail Family Transcriptional Repressor
1
T2DM Type 2 diabetes mellitus
TEC Tubular epithelial cells
TGF-β Transforming growth factor β
Th cells T helper cells,
Th1 T helper cell 1
Th2 T helper cell 2
Th17 T helper cell 17
TIMP-2 Tissue inhibitor of metalloproteinases-2
TNF Tumor necrosis factor
TRADD TNF-receptor dead domain
Treg Regulatory T cells
Twist1 Twist Family BHLH Transcription Fac-
tor 1
UUO Unilateral ureter obstruction
VEGF Vascular endothelial growth factor
Introduction
Acute kidney injury (AKI) is an enormous health burden
worldwide, and associated with end stage renal disease
(ESRD), cardiovascular diseases (CVD), hypertension and
death [1–3]. A recent meta-analysis including 154 studies
with more than 3.5 million AKI patients from mostly high-
income countries found a pooled incidence as high as 21.6%
and a mortality rate of 23.9% [4]. These numbers are even
higher for patients in intensive care units, where the inci-
dence is up to 50% [5]. In high-income countries, AKI is
mainly seen in hospitalized patients, whereas in low-income
countries, it is mostly community-acquired due to dehydra-
tion caused by gastroenteritis, acute infections and toxins
in combination with limited access to health care services
[6]. In 2015, the International Society of Nephrology (ISN)
stated the treatment of AKI as a human right [7].
AKI can result in a broad spectrum of renal outcomes
ranging from full recovery to ESRD. Historically, an
improvement in serum creatinine and blood urea nitro-
gen (BUN) was presumed full recovery of AKI. Over the
last decade, there is an appreciation that many cases of
AKI lead to the development of chronic kidney disease
(CKD). Even hospitalized patients with a small serum
creatinine increase (1.2 to < 1.5 times), that does meet
the AKI Kidney Disease Improving Global Outcomes
(KDIGO) guidelines 2012, have been shown to have a sig-
nificantly increased risk for CVD development and long-
term mortality [8]. In order to cover situations of kidney
injury that neither meet AKI (defined for the timeframe
Journal of Nephrology
Recurrence of AKI
Recovery
Sustained
reversal
Transient AKI
<48h
AKI<7d
AKD
Risk factors: Severity/frequency of AKI, albuminuria, age, gender, pre-exisng CKD, hypoalbuminemia, arterial
hypertension, heart failure, obesity and diabetes mellitus
Fig. 1  Range of renal outcomes following AKI. According to Kid-
ney Disease Improving Global Outcomes (KDIGO) guideline 2012,
acute kidney injury (AKI) is defined as an increase in serum creati-
nine (SCr) by 50% within 7 days or an increase in SCr by 0.3 mg/dl
within 2 days or oliguria. Chronic kidney disease (CKD) criteria are
abnormalities of kidney structure or function for > 90 days based on
cause, glomerular filtration rate (GFR) category, and albuminuria cat-
egory (CGA). Acute kidney disease (AKD) definition applies if AKI
criteria were met or GFR < 60  ml/min per 1.73 ­m2 for < 3  months
or a decrease in GFR by ≥ 35% or increase in SCr by > 50% for <
3 months occurred. AKD start point depends on which criteria apply
within the first 7 days) nor CKD criteria (defined for the
time > 90 days) the term acute kidney disease (AKD) has
been proposed [9–11] (Fig. 1). Though AKI is now rec-
ognized as an important risk factor for CKD, the extent to
which AKI contributes to the incidence of CKD remains
unknown. A recent meta-analysis of 82 studies including
more than 2 million patients showed an elevated risk for
hospitalized patients with AKI for new or progressive
CKD (HR 2.67, 95% CI 1.99–3.58), ESRD (HR 4.81, 95%
CI 3.04–7.62) and mortality (HR 1.8, 95% CI 1.61–2.02),
with an increased risk for CKD development following
an increased AKI stage [12]. Besides the severity of AKI,
its frequency, as well as albuminuria, age, gender, pre-
existing CKD, hypoalbuminemia, and other chronic dis-
eases like arterial hypertension, heart failure, obesity and
diabetes mellitus (DM) have been identified as risk factors
for AKI to CKD progression [13–17].
The high hospitalization rate of AKI leads to enormous
health care costs. In 2017, United States´ AKI costs were
estimated to be between $5.4 and $24 billion; in particular,
the in-hospital dialysis need during AKI was associated with
a cost increase of $40,000 per patient [18]. In a popula-
tion-based study on 239,906 adults hospitalized in Alberta
Death
Progression
Persistent AKI
CKD >90d
(retrospectively day 0–day 7). AKI and AKD are overlapping syn-
dromes. AKI can either be followed by adaptive repair processes
leading to recovery or maladaptive repair resulting in progression to
CKD. Hence, these processes are a continuum and multiple outcomes
in between full recovery and progression to CKD are known. AKD
has been defined as a syndrome covering the timeframe between AKI
and CKD. Known risk factors for AKI to CKD transition are severity
and frequency of AKI, albuminuria, age, gender, pre-existing CKD,
hypoalbuminemia, and chronic disease e.g. arterial hypertension,
heart failure and diabetes mellitus
(Canada), AKI-related healthcare costs were estimated to be
about 200 million Canadian dollars ($140 million) per year
[19]. Moreover, the progression from AKI to CKD leads to
comorbidity development and to a further medical expense
rise.
Given the heavy health burden of AKI and CKD, there
is an urgent need to develop treatments for AKI and to pre-
vent CKD. In this review, we provide a brief summary of
molecular mechanisms involved in maladaptive repair pro-
cesses causing AKI to CKD transition and their potential
interventions. We will also suggest possible approaches for
improvement of clinical strategies and patient follow up.
Mechanisms
Maladaptive repair causing AKI to CKD transition
involves many pathophysiological processes. Mechanisms
of renal fibrosis involve renal tubular epithelial cells and
the vascular system in the form of endothelial dysfunction
and microvascular rarefaction. Inflammation involving T
cells, B cells, macrophages, neutrophils, mast cells as well
13
 Journal of Nephrology

Fig. 2  Overview of different
mechanisms involved in AKI
to CKD progression. Different
etiologic agents concur in acute C O
kidney injury (AKI) pathogene- O
sis (upper half of the figure), the Sepsis
Post-renal
most common are: endogenous Ischemia
and exogenous toxins, ischemia/ Failure
Inflammatory
hypoxia, microbial products, Response
immune molecules (e.g. com-
plement fragments, interleukins,
chemokines), urinary tract
obstruction and factors related
to organ cross-talk (e.g. hor-
mones, cytokines, fluid unbal- Intrinsic
ance etc.) and multi-organ fail- AKI
ure. When the injury overturns Endo or Exogenous
the compensatory response,
Nephrotoxins
tissue repair is defective (lower Mulorgan
half). Angiogenesis is impaired,
failure
cell cycle becomes dysfunc-
tional, tubular epithelium loses
its intracellular structure and
dedifferentiates towards a myo- Maladapve Repair
fibroblast phenotype, the extra-
cellular matrix is expanded and
post-injury immune infiltrate
may persist. Altogether, these
factors cause the progression to Cell cycle arrest
chronic kidney disease (CKD). Organelle damage
EMT  Epithelial-mesenchymal
transition, EndMT Endothelial-
to-mesenchymal transition

Capillary rarefaction
EndMT
EMT, apoptosis,
senescence

Matrix expansion and remodeling

Inflammatory cell infiltraon

as dendritic cells (DCs) occurs (Fig. 2). However, there Cell death

are differences in the molecular mechanisms depending on
the etiology of AKI and, therefore, to which extent each
process contributes to the emerging fibrosis.
At least five different pathways can induce cellular death:
necrosis, apoptosis, necroptosis, ferroptosis and pyroptosis.
In AKI, acute tubular necrosis (ATN), seen commonly with
ischemic and toxic injury, is characterized by accumulation
of dead epithelial cells in the lumen with the classical muddy

13
Journal of Nephrology
brown casts. Most cases of ATN (except severe forms like
cortical necrosis) resolve with the classical sequence: oligo-
anuria plus AKI, improvement in urine output or polyuria
and decreases in serum creatinine. This common clinical
scenario parallels the proliferation of the surviving cells as
elegantly shown by cell-fate tracking. However, the putative
role of local stem elements is still questioned [20].
Regulated necrosis as well as apoptosis are mechanisms
involved in cell death in AKI. Two different pathways can
induce apoptosis: extrinsic and intrinsic. In the first case
immune cells release soluble mediators (e.g. tumor necro-
sis factor—TNF) or engage dead-receptor signaling (e.g.
Fas, a membrane homologue of TNF), thus activating cas-
pase-8. Intrinsic apoptosis occurs when intracellular injury
is irreversible and mitochondrial membrane is disrupted.
Consequently, cytochromes are released in the cytoplasm
and promote the assembling of the apoptosome, a qua-
ternary protein structure that activates caspase-9. Both
pathways converge on the sequential activation of cas-
pase-3, 7 and 6 and induce cell self-digestion and death.
Subsequently, immune scavengers phagocytize the remain-
ing apoptotic bodies without activating an inflammatory
response. In renal tubules, apoptotic cells are also shed in
the lumen and lost in urine.
Regulated necrosis in AKI includes necroptosis, fer-
roptosis, pyroptosis and G2/M cell cycle arrest. Necrop-
tosis is an immunogenic form of programmed cell death
and is activated by inflammatory cytokines, autophagy
failure and viruses expressing caspase-8 inhibitors. When
extrinsic apoptosis signaling prevails, receptor-interacting
protein kinase-1 (RIPK1) binds the TNF-receptor dead
domain (TRADD) and activates caspase-8. If the inflam-
matory signaling prevails (e.g. via interferon—IFN) or
caspase-8 is inhibited, RIPK1 binds protein kinase R and
phosphorylates RIPK3, which in turn activates mixed
lineage kinase domain-like protein (MLKL) and initiates
necroptosis. Of note, RIPK3 is a major determinant of
renal mitochondrial damage and is detectable in the urine
of patients with sepsis-AKI [21]. MLKL is overexpressed
by tubular cells following ischemia or tubular cast accu-
mulation and its inhibition is protective from AKI, and
MLKL can activate necroptosis in tubular epithelium inde-
pendently from RIPK3 [22].
Ferroptosis results from lethal lipid peroxidation due
to dysfunction of glutathione-peroxidase 4 and blocking
has been shown to protect from renal ischemic reperfusion
injury (IRI) in mice [23]. Another cell death pathway is
pyroptosis, a “hyper-inflammatory” cell death. Different
cells respond to inflammation by assembling multimeric
protein complexes called inflammasomes that cleave and
activate different cytokines and inflammatory caspases.
The description of the inflammasome response is beyond
the scope of this review. However, in brief, the canonical
inflammasome can be over-activated during AKI and lead
to pyroptosis with cell membrane fragmentation and mas-
sive release of IL-1β and IL-18 [24]. There is emerging
data describing an autoamplification loop fired by inflam-
matory processes and necrosis. This process—called
necroinflammation—plays a major role in tubular injury
[23].
Extracellular matrix (ECM)
Renal fibrosis is characterized by accumulation of extracel-
lular matrix (ECM) causing structural and therefore func-
tional damage of the kidney. Immune cells and tubular cells
release profibrotic factors after AKI, which results in the
activation and proliferation of myofibroblasts which pro-
duce ECM. The origins of myofibroblasts include endothe-
lial cells (Endothelial-to-mesenchymal transition, EndMT),
epithelial cells (epithelial-mesenchymal transition, EMT)
and potentially immune cells [25].
Endothelial‑to‑mesenchymal transition (EndMT)
Peritubular endothelial cells represent a critical target dur-
ing AKI. The alterations of endothelial function are mainly
driven by a decreased bioavailability of nitric oxide and lead
to dysregulated blood flow, increased vascular permeability
and inflammatory cell recruitment. Recent studies suggested
that EndMT plays a key role in capillary rarefaction and
CKD progression. EndMT is defined as the loss of typical
endothelial markers with the transition into a pro-fibrotic
phenotype [26]; this phenomenon is a key feature in both
ischemic and septic AKI [27, 28]. In a swine model of renal
IRI, the activation of complement cascade induced EndMT
via Akt (protein kinase B, PKB) pathway. Moreover, in vitro
the anaphylatoxins C3a and C5a downregulated endothelial
antigen expression and promoted a fibroblast-like pheno-
type [28]. As consequence, therapeutic strategies targeting
EndMT, such as complement inhibition or stem cell infu-
sion, may enhance adaptive repair, thus limiting AKI to
CKD progression.
(Partial) epithelial‑to‑mesenchymal transition (EMT)
Epithelial-to-mesenchymal transition (EMT) occurs when
terminally differentiated epithelial cells acquire a mesen-
chymal phenotype. According to the original renal model
of EMT, tubular cells lose epithelial markers and start
expressing mesenchymal ones and therefore trigger fibrotic
remodeling. Disruption of the cytoskeleton, breakdown of
epithelial adhesion and basement membrane and synthesis
of α-smooth muscle actin (α-SMA) have been described [29,
30]. However, studies assessing cell lineages in a unilateral
ureter obstruction (UUO) model as well as an IRI-model
13

resulted in contradicting findings and could not confirm
tubular epithelial cells to be the source for myofibroblasts.
Instead, pericytes and fibroblasts were found to develop
towards myofibroblasts [31, 32].
More recent findings revealed the concept of epithelial-
mesenchymal plasticity (EMP): a partial change in the
tubular-cell-phenotype towards mesenchymal status and
vice versa occurs in a cycle of dedifferentiation and repair.
Chronic triggers and tissue damage can disrupt this bal-
ance and lead to development of a permanent mesenchymal
phenotype. Cell cycle arrest has been found to be a major
mechanism. Cells remain in G2 phase and are unable to re-
differentiate as they do not pass the G2/M checkpoint. The
G2/M checkpoint is the last control step before cells start
mitosis. Traditionally this step was understood to be a con-
trol mechanism in response to DNA damage. In AKI to CKD
transition it was also shown that transforming growth factor
β (TGF-β), Snail Family Transcriptional Repressor 1 (Snai1)
and Twist Family BHLH Transcription Factor 1 (Twist1)
have been found to be major regulators in these pathophysi-
ologic pathways by inducing cellular arrest [33–35].
Interestingly, heparanase (HPSE) is an endonuclease
regulating fibroblast growth factor (FGF-2) and TGF-β and
has been demonstrated to negatively impact the development
of IRI-AKI induced EMT [36].
Tubular epithelial cell senescence
Renal tubular epithelial cells play a key role in post-AKI
transition to CKD. The identified mechanisms of this mala-
daptive repair include: cell cycle arrest in G2/M phase EMT
and increased production of profibrogenic factors [37]. All
these biological processes induce tissue fibrosis and tubular
senescence. The latter is a dysfunctional phenotype of tubu-
lar cells characterized by organelle rarefaction, loss of solute
carriers and upregulation of myo-fibroblast pathways like
Wnt4/β-catenin [38]. A further mechanism of renal senes-
cence is the down-regulation of the anti-aging molecule
Klotho. Klotho protein is expressed as membrane recep-
tor or released as soluble hormone by tubular convoluted
segments. Its precise mechanism of action is still unknown,
however, circulating Klotho downregulates TGF-β signaling,
promotes phosphate clearance and maintains both endothe-
lial and tubular physiologic phenotype [39, 40]. As reported
for endothelial cell dysfunction, complement activation has a
pivotal role in tubular injury: in a swine model of renal IRI,
C1 inhibitor preserved tubular Klotho expression and C5a
in vitro reduced Klotho expression through nuclear factor
’kappa-light-chain-enhancer’ of activated B-cells (NF-κB)
signaling and induced tubular senescence through epigenetic
mechanisms [38]. Consistently, decreased Klotho expression
in kidney allografts was associated with delayed graft func-
tion (DGF) and earlier functional loss [41].
13
Journal of Nephrology
Inflammatory processes
Although the inflammatory processes in AKI have been
extensively studied, the data on soluble inflammatory fac-
tors and immune cells contributing to AKI to CKD transi-
tion is limited. It is important to note that the data has to
be interpreted in the context of the experimental model. In
many studies, unilateral ischemic model is used, sometimes
with aggravation through following nephrectomy of the con-
tralateral kidney or high salt diet. Other common models
include the UUO and bilateral ischemic models. Chronic
changes—such as fibrosis—are often assessed after 6 weeks
[42]. Studies with more long-term follow-ups are rare. Stud-
ies on macrophages and DCs include glomerular as well as
interstitial fibrosis models which further complicates data
interpretation.
T cells—CD4+ and CD8+—infiltrate the kidney early
within hours after IRI, and have additional waves 5–6 weeks
later, when the expression of IL-1β and “regulated upon acti-
vation, normal T-cell expressed and secreted” (RANTES)—
as general inflammation markers occurs in IRI kidneys, com-
pared to contralateral and sham kidneys [42–44]. When T
cells from mice, that had undergone unilateral 60 min-IRI,
were adoptively transferred into WT mice, the histological
assessment showed no statistically significant difference in
fibrosis scores. However, a significant increase in albumi-
nuria was measured after 12 weeks compared to sham mice
[45]. Interestingly, T cells in spleen of IRI mice as well as
IRI-primed lymphocyte recipients showed changes suggest-
ing a systemic proinflammatory response—in mice with kid-
ney IRI, an increase of the proinflammatory cytokine Inter-
feron γ (IFN-γ) occurred in splenic T cells, even though
there were no changes in numbers [42]. In mice that had
undergone adoptive transfer of IRI-primed lymphocytes,
CD3+ and CD4+ lymphocytes, more specifically acti-
vated T cells (CD3+ CD25+) and memory T cells (CD4+
CD44+), were significantly elevated in spleen compared to
sham mice. These findings indicate a mechanistic role of
T cells in the pathogenesis of renal fibrosis following AKI
[45]. Depletion of CD4+ and CD8+ T cells 24 h before
unilateral ischemia resulted in less medullary damage and
reduced kidney IFN-γ expression. When depleting T cells
after ischemia, IL-1β in the kidney was upregulated [44].
When assessing CD4+ T cells in AKI, the T helper cell
(Th) 1 subset of CD4+ T cells has been demonstrated to
play a role in pathogenesis. An additional inflammatory
subgroup of CD4+ T cells—Th17 cells—mediates AKI to
CKD transition [46]. When treating rats with high salt diet
after AKI, an exacerbation was found. Interestingly, arterial
hypertension was found and CD4+ T cells showed higher
amount of activation and Th17, Th1 and Th2 subgroups in
rats treated with high salt diet. When unilateral nephrectomy
was performed, kidneys of rats that had been exposed to the
Journal of Nephrology
high salt diet, showed more fibrosis and cell volume in the
interstitium. Losartan treatment reversed these effects and
resulted in reduced CD4+ T cell kidney infiltration, includ-
ing Th17, Th1 and Th2 subgroups. However, the percentage
of activated or memory T cells was not affected [43]. Cal-
cium release-activated calcium channel protein 1 (Orai1) is
a subunit of Ca2+ release-activated C ­ a2+ (CRAC) channel,
a membrane protein involved in the control of intracellular
Ca2+ concentration. Orai1 was found to play an important
role in the mechanism of CD4+ IL17+ T cells in AKI patho-
genesis. Its expression is increased after AKI and subsequent
intracellular ­Ca2+ accumulation leads to an upregulation of
ROR𝛾T activity which induces skewing towards IL-17 pro-
ducing T cells. Blocking of Orai1 through YM58483/BPT2
resulted in attenuation of AKI and most importantly, to a
decrease in renal fibrosis.
Following AKI, B cell numbers increase in mouse kid-
neys and proliferation as well as differentiation into CD126+
plasma cells occurs [47]. B cell-deficient mice have been
shown to be protected from renal IRI, suggesting a patho-
genic contribution of B cells in AKI. However, adoptive
transfer of B cells into those B cell-deficient mice did not
restore the susceptibility to AKI, whereas transfer of serum
did [48]. In contrast, a study using a similar methodologic
approach described B cell-deficient mice to present worse
AKI with decreased IL-10 in serum [49]. After kidney
IRI, B cell-deficient mice present higher IL-10 and vascu-
lar endothelial growth factor levels, indicating that B cells
might block repair processes and therefore contribute to
fibrosis [47]. Overall, cellular and soluble response might
lead into different directions of repair and fibrosis. It might
also be the case that different subgroups of B cells represent
different roles in tissue fibrosis and repair processes [49].
T lymphocytes in mouse kidneys have been found months
after IRI and a population of CD19+ ∕low CD45R− B lympho-
cytes 16–18 months after bilateral IRI in the kidney with
high expression of IL-6-Receptor (CD126) and Cxcl12-
Receptor (CD184). Cxcl12 is expressed by renal stromal
cells in AKI to CKD transition. Tertiary lymphoid organs
occur in the kidney after IRI [50].
Macrophages also consist of different subgroups with
different roles in AKI and AKI to CKD transition. Tradi-
tionally, M1 macrophages are regarded as proinflammatory
and M2 macrophages are known to contribute to repair of
AKI. However, in sustained tubular injury, an uncontrolled
hyperproliferation of M2 macrophages occurs and CD11b +
Ly6C low macrophages, a profibrotic M2 macrophage sub-
population, is predominant [51]. Recruitment of fibroblasts
through ECM and pro-fibrotic factors as well as an increase
of matrix metalloprotease (MMP) expression contribute to
the development of renal fibrosis [52].
It can be difficult to differentiate kidney DCs and mono-
cytes/macrophages. In a model of glomerular disease, it
has been demonstrated that DCs aggravate progression
of kidney disease by promoting CD4+ T cell recruitment
[53]. However, in a UUO model, a direct role in tissue
fibrosis was not identified even though DCs were acti-
vated with a higher antigen presenting phenotype [54].
Cytokines that are produced by DCs are known to play
a role in maladaptive repair. The extent to which those
released by DCs contribute to fibrosis is unknown. In
human fibrotic kidneys, the number of DCs is elevated,
displaying a heightened expression of activation markers
and TGF-β production [55].
Albumin has been identified as a potential antigen in
rat CKD model that is reabsorbed from the tubules and
after proteasomal processing is presented by DCs leading
to activation of CD8+ T cells, that produce IFN-γ. Dam-
aged-associated molecular patterns (DAMPs) seem to be
required for this reaction since ovalbumin administration
in healthy mice kidneys did not lead to an proinflammatory
immune response [56]. Depleting CD8+ T cells alone was
also shown to decrease fibrosis following AKI as CD8+ T
cells ameliorate monocyte-to-fibroblast transition driven
by CD4+ T cells [57].
Mast cells are early responders of inflammation and
release large amounts of proinflammatory factors such
as cytokines, chemokines, growth factors, proteases and
profibrotic mediators (TGF-β, MMPs). Chymase, one of
the released proteases, has a unique role since it is also
involved in the activation of the angiotensin II pathway.
In steady state, there is only a small number of mast cells
found in the kidney, which increases during inflammatory
conditions and correlates with fibrosis—mostly in the
interstitium and rarely around glomeruli. There have been
conflicting outcomes using different knock out (KO) and
disease models suggesting the existence of different sub-
types of macrophages that require further observation [58].
Overall—similar to other immune cells described here—it
is believed that the pro-fibrotic phenotype rather occurs
in the setting of extended and chronic inflammation [59].
Besides CD4+ T cells, γδ T cells, macrophages, DCs
and natural killer (NK) cells are also known to release
IL-17, which promotes neutrophil invasion and therefore
renal fibrosis [60, 61]. Neutrophils accumulate in AKI
kidneys and depletion in an UUO mouse model leads
to decreased M2 macrophage invasion and less fibrosis.
Through production of neutrophil extracellular traps
(NET), which consist of pro-inflammatory cytokines, pro-
teases and chromatin, they might contribute to necrosis
in the kidney [23]. The pro-fibrotic roles of neutrophils
has recently been described to be MMP-9 dependent [62].
In contrast, several immune cells have been shown to
ameliorate fibrosis and contribute to tissue repair. Tregs
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 Journal of Nephrology

Tregs
Memory- Profibroc cytokines Monocytes
(CD44+), (TGF-β, IL-1 β, TNF,
Acvaon IL-6, IL-12)
DNs (CD25+),
IFN-γ, DCs M2
RANTES,
IL-1β Ag-presentaon repair

Acvaon (IL-4, IL-

B cells 6, Ag-presentaon) T cells M1 Macrophages
in early AKI
Acvaon
IFN-γ (IL-17)

CD8+
Profibroc
cytokines (NO,
Injury leads to TNFα, IL17)
release of IL-1, Il-6, Monocyte-to- M2
IL-17, IL-23, MCP-1, Promoon fibroblast ly6C low
B cells KC, IFN-γ CD4+ transion
Acvaon
CD19⁺/lowCD45R¯
Profibroc cytokines
Acvaon (TNFα, IL-4, IL-13)
IL-1 from monocytes, (IL-17) Transion
Acvaon NaCl promote MMP-9
(IL-6, differenciaon Neutrophils Mast Cells
Monoclonal Ab Cxcl12)
Profibroc Profibroc factors
Th1 Cytokines, (TGF-β1, PDGF, VEGF,
NET IGF1, Galacn3) Profibroc factors
Th17 Orai1 (TGF-β1, PDGF,
CTGF), Tryptase,
Chymas (AngII

Fibroblasts
acvaon)

Parenchymal
Transformaon/
acvaon
ECM
cells EMT,

Myofibroblasts
EndMT

Fig. 3  Immune cells involved in AKI to CKD transition. Various
immune cells contribute to pro-fibrotic processes in acute kidney
injury (AKI). Main mechanisms include the release of pro-fibrotic
cytokines and profibrotic factors. Additionally, differentiation towards
pro-fibrotic immune cell types and transition to fibroblasts or myofi-
broblasts have also been described. Immune cells that are involved
in AKI to chronic kidney disease (CKD) transition are marked blue
and blue arrows display differentiation into subgroups. Production of
pro-fibrotic cytokines, antigen-presentation and activation of other
immune cells are shown in orange. Other pro-fibrotic factors, that
are involved in myofibroblast-activation, are marked in brown. Cells
and pathways with anti-fibrotic functions are shown in green. DC
Dendritic cells, M2 M2 macrophages, Th1 T helper cell 1, Th17 T
helper cell 17, Treg regulatory T cells, DN αβTCR double negative
T cells, ECM Extra cellular matrix, Ag-presentation Antigen presen-
tation, RANTES Regulated upon activation, normal T-cell expressed
and secreted, Il interleukin, KC keratinocyte-derived chemokine,
MCP-1 Monocyte chemoattractant protein-1, MMP9 Matrix met-
alloprotease-9, NET Neutrophil extracellular traps, Cxcl12 CXC-
Motif-Chemokin 12, Orai1 Calcium release-activated calcium chan-
nel protein 1, PDGF Platelet-derived growth factor, VEGF Vascular
Endothelial Growth Factor, CTGF CCN2 or connective tissue growth
factor, IGF1 Insulin-like growth factor 1

have been investigated extensively. αβTCR double nega- several clinical trials. Data from experimental studies
tive T cells (DN) lack CD4 and CD8 receptors and have suggest administration of growth factors, anti-oxidants
been shown to benefit in AKI [63] (Fig. 3). Even though and anti-fibrotic molecules. However, clinical results are
there is lack of knowledge of the specific roles of most of still lacking given that translation from experimental to
these cells in AKI to CKD progression, they hold signifi- clinical studies has usually failed in AKI development
cant potential for positive effects with possible treatment and progression. Recent experimental studies suggested
options in kidney fibrosis and further research should be new potential tools and OMICS technologies allowed the
conducted. identification of new molecules and pathways involved in
AKI to CKD transition, which has led to the discovery of
new biomarkers, that should greatly assist clinical trials
Potential interventions in this area.
We arbitrarily highlight two promising approaches that
Different therapeutic strategies have been proposed to limit our teams are studying: The first is the modulation of the
AKI to CKD progression: Established options include low Kelch-like ECH-associated protein 1/Nuclear factor eryth-
salt and protein intake or pharmacological inhibition of roid 2-related factor 2 (Keap1/Nrf2) pathway: Nrf2 is one of
the renin–angiotensin–aldosterone system confirmed by the most relevant anti-oxidant and anti-senescent molecules

13
Journal of Nephrology
expressed by renal resident cells and immune cells, sug-
gesting its putative role in the mechanisms of immune-
kidney interaction associated with adaptive or maladaptive
repair following AKI. The second approach is based on the
expanding field of regenerative medicine: Stem cell-based
therapies are the cornerstone of regenerative medicine and
represent one of the ways to enhance tissue repair in acute
and chronic organ dysfunction. The field of stem cell therapy
has recently received a major advance from the observa-
tion that their regenerative potential is mainly ascribed to
the release of paracrine mediators. Among these paracrine
factors, extracellular vesicles (EV) represent a new way to
enlighten the mechanisms of cell-to-cell communication:
stem cell-derived EV have been evaluated in experimen-
tal and clinical studies as therapeutic approach for acute
and chronic organ injury. Recent reports shed light into
the mechanisms of EV biogenesis and formation and more
innovative protocols have been developed for isolation and
characterization of EV: for all these reasons, stem EV are
currently under evaluation in clinical trials as regenerative
strategy of several organs including the kidney.
Nrf2 modification
The Keap1/Nrf2 pathway is a promising therapeutic target
for kidney diseases. In steady state, Keap1 inhibits the activ-
ity of Nrf2, a major player in cytotoxic stress protection.
This connection is released by oxidative stress leading to an
upregulation of Nrf2 target genes. In AKI, a high oxidative
stress level occurs along with IRI [64] and CKD has been
shown to be associated with decreased Nrf2 activity [65].
Therefore, in both conditions an increase of the Nrf2 expres-
sion is considered a promising therapeutic strategy and dif-
ferent approaches, such as pharmacologic modulation and
gene editing, are being investigated in basic research studies
as well as clinical trials [66].
In murine model, Keap1 whole body KO mice are not
viable, but the hypomorphic mutant has been shown to be
protected from AKI and to develop less fibrosis, indicating
a beneficial effect of Nrf2 upregulation for AKI to CKD
transition in a murine model [67]. Tissue specific KO of
Keap1 gene protects from AKI: Keap1-KO in immune cells
was shown to ameliorate AKI [68]. However, deleting Keap1
in adult tubular cells may be a viable option with potential
for protection [67]. Yet, there is data showing that Keap1
gene in tubular epithelial cells may be involved in homeo-
stasis and development of the kidneys. Kidney epithelial cell
specific Keap1-KO resulted in hydronephrosis, suggesting
Keap1 gene to play an important role in development of kid-
neys, particularly when water/Aquaporine 2 (AQP2) trans-
port is impaired [69, 70]. Thus, caution is necessary when
deciding which cell type to edit.
Pharmacologic Nrf2 activators have shown promising
benefit in mouse and human studies. Systemic administration
of CDDO-imidazole (CDDO-Im) protected mice from AKI.
However, contrasting effects using high dosage of CDDO-
9,11-dihydro-trifluoroethyl Amide (CDDO-dhTFEA) have
been described and kidney fibrosis was worsened, potentially
through an activation of NF-κB, which is also regulated by
Keap1. CDDO-methyl ester (CDDO-Me) has been already
used in clinical trials for treatment of patients with renal dis-
eases and has been shown to increase eGFR in type 2 diabe-
tes mellitus (T2DM) patients with CKD stages 3–4 (BEAM
study). However, adverse cardiovascular effects occurred in
a similar study including T2DM participants with advanced
CKD stage 4 (BEACON study). Additionally, an increase of
albuminuria was observed in both studies [66].
Since T cells could be a direct mediator of AKI to CKD
progression, they constitute a particularly attractive thera-
peutic target. It could be shown, that adoptive transfer of T
cells from Keap1- KO mice leads to protection from AKI in
the recipient mice [68]. However, whether this approach is
also applicable to prevent AKI to CKD progression has yet
to be investigated. Successful Keap1-KO using CRISPR/
Cas9 technique in human T cells has already been demon-
strated and might pave the way for future immunotherapy
[71].
Regenerative role of stem cell‑derived extracellular
vesicles (EVs)
Different types of stem cells have been investigated as
potential therapeutic strategy in experimental models of
AKI: However, the results of clinical trials mainly based
on mesenchymal stromal cell (MSC) administration to pre-
vent AKI in patients at high risk after cardiac surgery were
conflicting. Recently, it has been shown that the regenera-
tive potential of stem cells is primarily ascribed to parac-
rine mechanisms including the release of growth factors
and EVs. EVs are microparticles released by different
types of progenitors and able to induce epigenetic repro-
gramming of injured renal cells through the direct transfer
of proteins, lipids, mRNA and microRNA [72]. Compared
to cellular therapies, EVs have minimal immunological
and neoplastic risk while being extremely malleable. Most
of stem cell derived EVs do not express major histocom-
patibility complex (MHC) molecules, thus can be repeat-
edly infused without inducing allo-immunization. Vesicle
content varies according to the parental cell phenotype and
culture conditions and, as EVs do not carry coding DNA,
parental gene editing may enhance specific EV proprieties
without substantial risk of transformation in target cells
[73]. Various EV types have been tested as therapeutic
tools in pre-clinical models of AKI; given the kidneys
being mesodermic organs, most studies have investigated
13
 Journal of Nephrology

Table 1  Pre-clinical studies about extracellular vesicles (EVs) as acute kidney injury (AKI) therapy
Author References EV source AKI model Mechanism

C. Wang [76] HSC IRI miR-199a-5p inhibits ER stress in tubular cells

T. Pan [77] myocytes Sepsis miR-21 inhibits Nf-κB and PTEN in tubular cells
X. Wu [78] BC-SC Cardiac surgery Reduced inflammatory infiltration
J.L. Viñas [79] EPC IRI miR486-5p transfer promotes regenerative cell chemotaxis
J.M. Dominguez 2nd [80] TEC IRI Modulation of > 300 proteins differentially expressed in IRI
G. Zhang [81] Kidney vein—TEC IRI Apoptosis downregulation
B. Wang [82] MSC Cisplatin Autophagy induction
A. Ranghino [83] Glom MSC IRI miRNA modulation (most upregulated: hsa-miR-299-5p)
J.H. Dominguez [84] TEC IRI IRI altered transcript were reduced from 3100 to 1600
S. Bruno [85] MSC Glycerol miRNA transfer, miR-486-5p most enriched
X. Zou [86] MSC IRI Downregulation of NK cell migration to kidneys
X. Zou [87] MSC IRI VEGF and angiogenesis upregulation
G. Zhang [88] BC-SC IRI Nrf2 and heme oxygenase 1 upregulation
J. L Viñas [89] EPC IRI miR486-5p transfer curbs PTEN activation
B. Shen [90] MSC IRI CCR2 exosome clear CCL2 and prevent macrophage migration
K.C. Lin [91] ASC IRI Apoptosis downregulation
D. Gu [92] MSC IRI miR-30 inhibits mitochondrial damage
D. C. de Almeida [93] MSC Cisplatin miRNA transfer (miR-880, miR-141, miR-377, and miR-21)
reduces apoptosis
G. Q. Ju [94] MSC IRI HGF induction via miRNA transfer
D. Burger [95] EPC IRI Apoptosis inhibition
X. Zou [96] BC-SC IRI Suppression of CX3CL1
G. Zhang [97] BC-SC IRI Downregulation of inducible NO synthase
M.B. Herrera Sanchez [98] LSC Glycerol Improvement of tubular proliferation
H. Y. Choi [99] Kidney SC IRI Transfer of growth factor RNA (VEGF, bFGF etc.)
Y. Zhou [100] BC-SC Cisplatin ERK pathway upregulation
L. Kilpinen [101] BC-SC IRI Transfer of growth factors
V. Cantaluppi [74] EPC IRI Angiogenic miRNA (miR-126 and miR-296) delivery
S. Bruno [102] MSC Cisplatin Apoptosis inhibition
S. Gatti [103] MSC IRI miRNA transfer, apoptosis inhibition
S. Bruno [104] MSC Glycerol EVs adhere to tubules via CD44 and induce tubular cell pro-
liferation
V. Cantaluppi [105] EPC Glomerulonephritis Complement inhibition via miRNA transfer

AKI Acute kidney injury, ASC Adipose mesenchymal stem cells, BC-SC Blood cord (Warton Jelly) stem cells, bFGF Basic fibroblast growth
factor, CCL2 CC-chemokine ligand 2, CCR2 C–C chemokine receptor type  2, EPC Endothelial progenitor cells, ER Endoplasmic reticulum,
ERK 1/2 Extracellular-signal-regulated kinase 1/2, EVs Extracellular vesicles, Glom Glomerular, HGF Hepatocyte growth factor, HSC Hemat-
opoietic stem cells, IRI Ischemia reperfusion injury, LSC Liver stem cells, MSC Mesenchymal stem cells, NK cells Natural Killer cells, NO
Nitric oxide, Nrf2 Nuclear factor erythroid 2-related factor 2, PTEN Phosphatase and Tensin homolog, TEC Tubular epithelial cells, VEGF Vas-
cular Endothelial Growth Factor

EVs of mesenchymal origin, including MSC, hematopoi-
etic SC (HSC), endothelial progenitors and tubular cell
lines (Table 1) [74, 75]. A recent meta-analysis on EV
therapy in experimental AKI was performed. However,
the paper was limited by the heterogeneity of pre-clinical
investigations and acknowledged a significant publication
bias [75]. Nevertheless, 31 studies met the pre-specified
quality criteria and the authors found that stem cell EVs
(mainly from MSC) consistently improved renal function
and histology during AKI and reduced the inflammatory
burst. Of note, EV infusion was non-inferior to stem cell-
based therapies without potential adverse effects such as
tumorigenesis and maldifferentiation (Table 1). In experi-
mental renal IRI, EVs from endothelial progenitors local-
ized in both the renal peri-tubular capillaries and tubular
epithelial cells and prevented AKI to CKD progression. Of
note, both RNAse treatment of EVs and silencing of Dicer
(a key enzyme in microRNA biogenesis) in origin cells

13
Journal of Nephrology
Fig. 4  Stem cells and extracellular vesicles as treatment options for
AKI. Various stem cell types have been investigated in preclinical
models to treat acute kidney injury (AKI). Bone marrow stem cells
(SC) and progenitors are by far the most studied and include endothe-
lial progenitor cells, mesenchymal SC and hematopoietic SC. Other
sources are: blood cord, embryonic tissue, various mesenchymal tis-
sues (including adipose SC), kidney progenitors (that express CD133
surface marker) and the induced pluripotent SC (usually obtained
completely abrogated this protective effect. These results
suggest the key role of RNA transfer from EVs to target
cells in order to facilitate kidney repair [74] (Fig. 4). Bas-
ing on these results, stem cell-derived EVs may represent
an intriguing option for limiting AKI to CKD progression.
Clinical interventions
In order to address optimal care for the high-risk popula-
tion of AKI patients, attempts have been made for improve-
ment in clinical management. Most importantly, the need
for preventive actions and early detection measures has to be
emphasized. This could enable proactive management and
anticipation of disease progression.
with a viral transfection of specific oncogenes). SC can be directly
infused as therapeutic agents or can be cultivated to collect their ben-
eficial soluble factors. In particular, extracellular vesicles can be iso-
lated by ultra-centrifugation or specific enrichment membranes. BM
bone marrow, SC stem cells, EPC endothelial progenitor cells, MSC
mesenchymal stem cells, HSC hematopoietic stem cells, BC blood
cord, ASC adipose stem cells, iPS induced pluripotent stem cells, EV
extracellular vesicles
To pave the way for timely diagnosis of AKI and evalu-
ation of prognosis, clinical multivariant models as well as
novel biomarkers have been investigated.
Hodgson et al. recently summarized efforts of the past
decades regarding prediction models and AKI alerts and
concluded that early diagnosis of AKI can only improve
outcomes if adequate interventions follow. In a prospective
cohort analysis, the outcome of patients suffering from hos-
pital-acquired AKI could be improved using this approach.
A sophisticated flow chart advised for actions depending
on the risk level, such as further assessment of underlying
disease and fluid status, further blood and urinary labora-
tory assessments, imaging, reviewing of drugs, and patient
education. However, study participants with community-
acquired AKI showed no benefit, which, according to the
authors, might be due to lack of correct documentation of
13

kidney risk factors before hospital admission. The impor-
tance of a transfer of information between primary and sec-
ondary care systems was emphasized [106]. Another review
similarly found that the combination of care bundles, e-alerts
and education led to the best outcomes [107]. Patients under
intensive medical care, benefited from a recently developed
risk prediction score [108, 109].
The current gold standard for AKI diagnosis is still rep-
resented by serum creatinine, which has major limitations
since it detects AKI on an advanced stage and gives no
insight in the underlying pathogenesis. In order to evalu-
ate the risk for AKI to CKD transition, it would be par-
ticularly useful to find novel biomarkers that detect early
stages of AKI and provide information about maladaptive
repair processes. Following these approaches, not only have
biomarkers displaying early AKI as well as tubular injury
and inflammatory processes been the subject of research,
but also prognostic markers that help distinguish following
adaptive repair and fibrosis. Urinary neutrophil gelatinase-
associated lipocalin (NGAL) is already used in clinical
practice in Europe and Asia as a marker of early tubular
injury. Furthermore, kidney injury molecule-1 (KIM-1) has
been investigated as a tubular injury biomarker and its abil-
ity to predict development of CKD has been demonstrated.
However, for CKD progression of advanced stages of CKD
following AKI insults, advantages over established mark-
ers were not found. Tissue inhibitor of metalloproteinases-2
(TIMP-2) and insulin-like growth factor-binding protein 7
(IGFBP7) are commercially available urine biomarkers that
are used for AKI risk assessment in critically ill patients and
harbor potential for further clinical applications. As poten-
tial detectors of inflammatory processes proinflammatory
cytokines (e.g. IL-18, IL-6, IL-10), monocyte chemoattract-
ant protein-1 (MCP-1) and TNF receptors are investigated.
For distinction of adaptive and maladaptive repair, there is
urinary procollagen type III N-terminal peptide (PIIINP),
which is a product of collagen synthesis and might be a
promising representator of kidney fibrosis. Yet, urinary
epidermal growth factor (EGF) is inversely correlated with
interstitial fibrosis and shows potential as a biomarker rep-
resenting renal repair processes [110].
Additionally, consistent follow up management of AKI as
secondary or tertiary preventive measures is required. Thus,
several interesting studies have been performed to investi-
gate patient and health care provider awareness after AKI.
It has been shown that the majority of patients with AKI
lack awareness of their condition as well as knowledge of
risk factors after hospital discharge [16]. Additionally, the
compliance of patients for nephrological follow-ups after
hospital discharge is very low, although it has been demon-
strated that automatic scheduling can improve this issue. The
same study also stated 70% of the observed patients required
at least one intervention, emphasizing the importance of
13
Journal of Nephrology
follow-up visits in this collective [111, 112]. Harel et al.
found decreased mortality in AKI patients that were under
nephrological care [113]. Nonetheless, causality has not
been validated.
Due to limited evidence, there is no detailed guideline
yet for the management of AKI survivors. The current
KDIGO guideline recommends an evaluation of patients
three months after AKI [114]. The Acute Disease Quality
Initiative (ADQI) suggests the intensity and frequency of
surveillance be proportionate to the risk of future outcomes.
The follow-up management recommendations include
patient education, medication reconciliation, nephrotoxin
avoidance, and kidney function monitoring [9]. Basing on
the previous considerations, the AKI and continuous renal
replacement therapy (CRRT) Project Group of the Italian
Society of Nephrology (SIN) started an ongoing study with
the following aims: (1) to evaluate the “real-life” AKI inci-
dence in hospitalized patients; (2) to start a collaborative
program between Nephrologists and General Practitioners
for an integrated strategy of AKI follow-up; (3) to create a
biobank for the early identification of biomarkers of AKI to
CKD progression.
Conclusion
AKI is an increasingly recognized risk factor for CKD devel-
opment and progression. There have been developments in
elucidating the molecular and cellular mechanisms involved
in maladaptive repair processes revealing possible targets
for treatment. In addition, approaches in public health, pre-
diction models and clinical care initiatives have also been
studied with promising results. To decrease of AKI to CKD
progression worldwide, a combination of all these strategies
will be necessary. However, further research is required to
make a major impact to help our patients with AKI to CKD
progression.
Funding  This study was (partially) funded by the Italian Ministry of
Education, University and Research (MIUR) program “Departments of
Excellence 2018-2022”, AGING Project—Department of Translational
Medicine, Università del Piemonte Orientale (UPO). HR was supported
by grants from the NIDDK and philanthropic gifts from Rogelio Miro
and Sammy Eldin. JTK was supported with a scholarship by the Dr.
Werner Jackstädt-Foundation (project number S 134–10.117).
Compliance with ethical standards 
Conflict of interest  The authors have declared that no conflict of inter-
est exists.
Ethical approval  This article does not contain any studies with human
participants performed by any of the authors.
Journal of Nephrology

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