Sfad 097

Download as pdf or txt
Download as pdf or txt
You are on page 1of 12

Clinical Kidney Journal, 2023, vol. 0, no.

0, 1–12

https:/doi.org/10.1093/ckj/sfad097
Advance Access Publication Date: 24 April 2023
CKJ Review

CKJ REVIEW

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


Chronic kidney disease in children: an update
Luigi Cirillo1,2 , Letizia De Chiara2 , Samantha Innocenti1 ,
Carmela Errichiello1 , Paola Romagnani1,2 and Francesca Becherucci 1,2

1
Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy and 2 Department of
Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence, Italy
Correspondence to: Francesca Becherucci; E-mail: francesca.becherucci@meyer.it

ABSTRACT
Chronic kidney disease (CKD) is a major healthcare issue worldwide. However, the prevalence of pediatric CKD has never
been systematically assessed and consistent information is lacking in this population. The current definition of CKD is
based on glomerular filtration rate (GFR) and the extent of albuminuria. Given the physiological age-related modification
of GFR in the first years of life, the definition of CKD is challenging per se in the pediatric population, resulting in high
risk of underdiagnosis in this population, treatment delays and untailored clinical management. The advent and
spreading of massive-parallel sequencing technology has prompted a profound revision of the epidemiology and the
causes of CKD in children, supporting the hypothesis that CKD is much more frequent than currently reported in
children and adolescents. This acquired knowledge will eventually converge in the identification of the molecular
pathways and cellular response to damage, with new specific therapeutic targets to control disease progression and
clinical features of children with CKD. In this review, we will focus on recent innovations in the field of pediatric CKD and
in particular those where advances in knowledge have become available in the last years, with the aim of providing a
new perspective on CKD in children and adolescents.

LAY SUMMARY
Chronic kidney disease (CKD) is a devastating disease for which no cure is currently available. Lack of awareness,
genetic predisposition and difficulties in measuring kidney function as a tangible sign of CKD in the pediatric
population have contributed to delay the identification of effective treatments as well as the causes behind disease
progression. In this review, we provide an up-to-date description of the most recent findings in terms of hereditary
disorders, pathological mechanisms, novel therapeutic options and nutritional evaluations in children with CKD. We
will also discuss the most recent advancements and challenges in effectively determining kidney function in young
patients. Collectively, we aim to provide a novel perspective on CKD in children to boost the translation into clinical
practice of the most recent discoveries.

Keywords: chronic kidney disease, genetics, innovative therapies, nutrition, pediatric

Received: 22.1.2023; Editorial decision: 27.3.2023


© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution,
and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

1
2 Chronic kidney disease in children

INTRODUCTION populations [13]. As for those used in the adult population [e.g.
Modification of Diet in Renal Disease (MDRD), Chronic Kidney
Chronic kidney disease (CKD) is a major healthcare issue
Disease Epidemiology Collaboration (CKD-EPI), FAScrea/cysC , etc.],
worldwide. Recent estimates report that at least 10% of the
this equation has some limitations. It loses accuracy in sub-
general adult population is affected by a certain degree of CKD
jects with mGFR >75 mL/min/1.73 m2 and hyperfiltration [14],
[1, 2] and similar projections are becoming available in children
potentially resulting in relevant treatment delay [15]. The small
[3]. However, the prevalence of pediatric CKD has never been
proportion of patients <5 and >15 years old in the testing cohort
systematically assessed and consistent information is lacking
represented an additional flaw. To overcome these limitations,
in this population. Currently available data are derived primarily
in 2021 a new equation (named CKiD U25) was validated from
from kidney replacement therapy registries in Western coun-
data of the Chronic Kidney Disease in Children study enrolling

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


tries [4, 5], thus significantly underestimating the global burden
patients up to 25 years old [16]. It employs serum creatinine and
of disease. Providing patients with appropriate management
cystatin C, patient age and gender without including height,
and therapies along with defining the actual CKD prevalence in
therefore avoiding the issue of anthropometric data as limiting
children represent unmet medical needs that urgently require
factors of the bedside Schwartz’s equation. CKiD U25 proved
solutions. The current definition of CKD is based on glomerular
to be more reliable in assessing CKD in adolescents and young
filtration rate (GFR) and the extent of albuminuria [6], which
adults in comparison with the other previously used equations
have proved to reliably predict long-term outcomes in adults
[16], which were shown to underestimate (Schwartz formula) or
[1]. Given the physiological age-related modification of GFR in
overestimate (CKD-EPI) GFR [17]. Of note, CKiD U25 was shown
the first years of life, the definition of CKD is challenging per se
to better intercept initial eGFR decline during adolescence in
in the pediatric population. Moreover, pediatric CKD presents
healthy children, making it a candidate for a promising tool for
an additional complexity represented by an extremely variable
CKD screening in this population [18].
spectrum of clinical presentations, ranging from completely
In solitary functioning kidney, renal length is considered as
silent disease (common for structural disorders) to severe
surrogate of kidney function in the first years of life [19]. An
kidney function impairment that markedly affects the life ex-
updated ultrasound-based kidney length normative value based
pectancy and quality of life of patients and their caregivers [7].
on body weight and surface area in addition to age and gender
The advent and spreading of massive-parallel sequencing (MPS)
was recently proposed to increase accuracy [20]. These aspects
technology has recently opened an interesting opportunity to
highlight the importance of linking kidney function with kidney
promote a revision of the epidemiology of CKD in children,
structure and nephron endowment in young patients who may
supporting the hypothesis that CKD is much more frequent
have not yet developed hypertension or albuminuria, early
than currently reported in children and adolescents. As in other
markers of kidney impairment. Since these patients often have
fields of medicine, genetics is pushing our understanding of
“normal” values of serum creatinine and eGFR, it could be
the pathomechanisms of kidney diseases. Ideally, this acquired
incautiously claimed that they do not present “implications
knowledge will eventually converge in the identification of the
for health” related to CKD. However, recent studies suggest a
molecular pathways and cellular response to damage, with new
not negligible risk of CKD that emerges in late adolescence
specific therapeutic targets to control disease progression and
and middle-adulthood [21, 22]. These observations support
clinical features of children with CKD.
the need to consider these patients at risk of developing CKD
In this review, we will focus on recent innovations in the
and to promote disease awareness to limit the number of
field of pediatric CKD and in particular those where advances
missing diagnoses [21]. New cutting-edge research and imaging
in knowledge have become available in recent years: (i) the chal-
techniques (e.g. multiparametric magnetic resonance imaging,
lenge of measuring kidney function and defining CKD in the pe-
positron emission tomography, etc.) are being implemented
diatric population; (ii) the impact of genetics in the clinical man-
to better define the kidney function, nephron number and
agement and in the epidemiology of pediatric CKD; (iii) the novel
hence prognosis [23–25]. Until then, surrogate indicators like
insights into mechanisms of CKD progression in children; (iv)
prematurity, low birth weight (LBW) and pregnancy stressors
the role of nutrition in balancing CKD progression and growth;
will still be essential to identify children at risk of CKD [26].
and (v) the new therapeutic options for pediatric CKD. By bring-
The assessment of kidney function has many limitations in
ing together the most recent advances in those fields, we will
newborns. Serum creatinine is an unreliable marker in the first
provide a new perspective on CKD in children and adolescents.
72 h of life, as it crosses the placental barrier, mostly reflect-
ing maternal values [27]. Cystatin C represents a valuable al-
ternative [28]. Furthermore, in newborns GFR is physiologically
THE CHALLENGE OF ASSESSING KIDNEY
<60 mL/min/1.73 m2 , reflecting organ maturation rather than
FUNCTION IN CHILDREN
kidney damage. A recent meta-analysis showed that the trend
The 2012 KDIGO guidelines define CKD based on cause, GFR and of GFR has a biphasic increase, doubling in the first 5 days of
albuminuria [8]. Beyond its apparent simplicity, this definition life (from 19.6 to 40.6 mL/min/1.73 m2 ), with a subsequent grad-
presents some challenges and pitfalls that are peculiar to the ual increase to about 60 mL/min/1.73 m2 by 4 weeks of age, then
pediatric population. reaching an asymptotically maturation by 18–24 months [29]. An
GFR can be measured (mGFR) using exogenous markers by updated k coefficient for Schwartz’s equation and new reference
iohexol and iothalamate clearance or renal scintigraphy [9–12]. intervals for serum creatinine and blood urea related to gesta-
However, these investigations are costly, time-consuming and tional age have been proposed for this group [30]. The same au-
relatively difficult to perform, with limited applicability in thors described an association between some maternal comor-
clinical practice. Therefore, equations using serum creatinine bidities (e.g. pre-eclampsia, diabetes, CKD, hypertension, etc.)
have been developed to estimate GFR (eGFR). In the pediatric and higher newborns’ serum creatinine and urea levels suggest-
setting, the most widely used equation is the 2009 revised ing that maternal conditions should be considered on kidney
bedside Schwartz’s formula, which estimates GFR from serum function evaluations in newborns and infants [30]. Preterm in-
creatinine, patient’s height and a constant (k) for all pediatric fants have a slower maturation of kidney function with a higher
L. Cirillo et al. 3

CA
KU
Albuminuria (ACR) T

CKD

s
eGFR A1 A2 A3

ie
ath
stage ml/min/1.73 m2 (< 30 mg/g) (30–300 mg/g) (> 300 mg/g)

nephrotoxic drugs, reduced kidney size, genetic


46%

top
abnormalities, low nephron endowment, etc.

ocy
G1 ≥ 90

Pod
40%

LBW, prematurity, previous AKI,


G2 60–89 10% 28%
3%
G3a 45–59

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


meta thies/
5%

HUS
3%

disea olic
ses
G3b 30–44

ulopa
76%

b
13%

Tub
G4 15–29
56% 29%

Cy
G5 < 15

s ti
cd
ea

is
se
LBW, prematurity, previous AKI, s
nephrotoxic drugs, reduced kidney size, genetic us
eo
abnormalities, low nephron endowment, etc. ll a n
Mis ce
Figure 1: Staging of CKD in children and adolescents. This picture illustrates CKD
definition and staging according to KDIGO guidelines. This definition is based Figure 2: Causes of CKD in children and young adults and frequency of genetic
on eGFR and proteinuria. Colors (from green to red) refer to the risk of progres- forms. The inner circle represents the primary kidney disease distribution in
sion toward kidney failure. Additional clinical features and events significantly percentage at the start of kidney replacement therapy in Europe in the pediatric
increase the risk of developing CKD and staging worsening in the pediatric pop- population (data from ESPN/ERA-EDTA Registry, Annual Report 2018). The outer
ulation. These features need to be taken into account in order to properly assess circle represents the proportion of genetic diagnosis according to each group of
and stage CKD in children and adolescents. ACR, albumin-to-creatinine ratio. diseases (data from [45, 58, 62, 163–165]). HUS, hemolytic–uremic syndrome.

risk of neonatal acute kidney injury (AKI) and lifelong CKD [31– ical practice [39, 40]. Pediatric nephrology represents the field
33]. In the most recent years, pediatric nephrologists and neona- where this knowledge was initially built. According to epidemi-
tologists have made significant efforts to raise awareness about ology and registry data, the primary cause of CKD and kid-
neonatal AKI and to prevent its occurrence [34]. When suspect- ney failure differ in the pediatric and adult population [41, 42].
ing CKD in newborn/infants, an accurate evaluation of the trend In children and young adults (i.e. younger than 25 years old)
of GFR would probably allow an early identification of an altered congenital anomalies of the kidney and urinary tract (CAKUT),
nephron recruitment or low endowment. Moreover, cystatin C steroid-resistant nephrotic syndrome, chronic glomerulonephri-
could be more accurate than serum creatinine for GFR estima- tis and ciliopathies account for >70% of cases [3, 43]. These
tion in the first month of life, especially in preterm born and very disorders show a monogenic cause in 10%–60% of cases [43–
LBW neonates, with values >2 mg/dL likely suggesting AKI or 45] (Fig. 2). Since copy number variations account for an ad-
reduced eGFR setting aside the need for urinary output or eGFR ditional proportion of cases, the role of genomics in pediatric
using serum creatinine [35]. CKD can be underestimated [39, 40]. This is particularly rele-
In conclusion, although many useful tools to estimate kidney vant for CAKUT [46]. Variants in intronic and regulatory regions
function are available in the pediatric population, physicians are or in genes modulating chromatin organization probably repre-
called to identify the correct method for each patient (Fig. 1), and sent additional sources of genetic predisposition [26]. These data
clinical features are essential for a global and accurate evalua- have been strengthening the concept that CKD and kidney fail-
tion. ure can be of genetic etiology in children, making genetic testing
a key tool in the diagnostic pathways of patients, thus informing
CHANGING THE LANDSCAPE OF PEDIATRIC prognosis, treatment options and familial counseling, together
with epidemiology [39].
CKD: THE ROLE OF GENETICS
The application of genomic strategies in pediatric patients
The technological revolution that has been progressively re- with CKD has provided support to understanding that mono-
placing traditional Sanger sequencing with MPS represents genic forms of kidney disorders are not exclusive to children.
the foundation of the “genomic era” in clinical medicine, in- Recently, few studies explored the role of genetics in adult
cluding nephrology. The impressive expansion of the num- nephropathies and CKD [47–52], with conflicting results. Differ-
ber of genes associated with specific kidney phenotypes (e.g. ences in diagnostic yields are due to nonuniform selection cri-
steroid-resistant nephrotic syndrome, primary tubulopathies, teria, sequencing strategies [i.e. gene panels, exome sequenc-
nephronophthisis, atypical hemolytic–uremic syndrome, etc.) ing (ES), etc.], bioinformatic analysis and variant prioritization.
promoted the introduction of genetic testing with MPS in clin- Though better performances have been obtained in cohorts of
ical practice, with the aim of defining etiological clues under- patients with specific phenotypes or diseases, genetic testing
lying clinical pictures, and to inform prognosis and therapeutic has clearly shown utility also in dissecting the cause of CKD of
management [36]. To date, more than 600 genes are listed as the unknown origin (CKDu) [53, 54]. Of note, genetic testing with ES
cause of kidney diseases, with almost monthly updates [37, 38]. proved to have ,efficacy in detecting a monogenic cause of CKD
Currently available sequencing platforms allow clinicians to ex- in a large unselected population of adult patients with kidney
plore them simultaneously, with relevant implications for clin- diseases, providing a diagnostic yield of nearly 10% [52].
4 Chronic kidney disease in children

While disease awareness about genetic forms of CKD is cer- [71–73]. This condition in conjunction with other risk factors
tainly robust among pediatric nephrologists, how to integrate (AKI or genetic predisposition) can promote CKD development
genetic testing in routine clinical practice, together with cost at any stage [74]. Defects in nephron differentiation [75] or de-
concerns, are still debated aspects that risk representing a bot- pletion of progenitor stem cell pool [76] account for some of the
tleneck to further implementation in daily clinical practice [45, cellular mechanisms leading to CAKUT, the major contributor
47, 53]. As an answer to the constantly increasing demand of to CKD in children [77]. This scattered progenitor population is
genetic testing in patients with CKD, organizations and health- maintained also in the adult kidney, but its ability to replace lost
care systems have been trying to set up service delivery mod- cells after damage is rather limited [78], implying that the kidney
els for the optimization of genomic strategies into routine prac- has to adapt to an injury rather than fully regenerate. Despite
tice [55]. Although providing significantly different results, these this, children and young adults have a remarkably higher capac-

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


preliminary experiences agree upon the clinical utility of ge- ity to withstand kidney injury in comparison with adults [79, 80].
netic testing in patients with kidney diseases and CKD [49, 50, This is thought to be mostly due to the higher renewal capacity
56–60]. An economic evaluation showed that early ES is effec- of progenitor cells in childhood [77] which declines over time but
tive in diagnosing monogenic kidney disease and leads to sub- is impaired in patients with congenital abnormalities affecting
stantial cost savings in children with glomerular disorders [49, these cells. Lost nephrons are then replaced by fibrotic tissue to
61]. We recently confirmed these data in a large cohort of pa- maintain kidney architecture and these structural changes mark
tients with CKD, where the prospective application of a clini- CKD development [81].
cal workflow based on patient selection, genetic diagnosis by The classical view regards the glomerulus as the epicenter
ES, reverse-phenotyping and multidisciplinary board discussion, of kidney disease progression while tubular injury is generally
provided a diagnostic rate as high as 67% irrespective of pa- considered secondary to glomerular involvement [82]. Nonethe-
tient’s age, and proved to be cost saving [62]. These observa- less, diseases originating in the glomerulus account for a rel-
tions have important implications for optimizing the use of atively small portion of CKD in children [83]. These patients
diagnostic investigations. Future perspectives are represented progress more quickly to kidney failure and are generally older
by longitudinal, cross-sectional, prospective, long-term studies at disease onset when compared with children affected by other
assessing efficacy and cost-effectiveness of genomic-first ap- causes of CKD [84]. In contrast, diseases that primarily affect the
proaches to CKD. In the next future, they will include whole- tubulo-interstitial compartment (e.g. CAKUT, ciliopathies, tubu-
genome sequencing to improve diagnostic efficacy. Prelimi- lopathies, etc.) account for the majority of cases of CKD in chil-
nary results including rare kidney diseases have already been dren and usually show a slow progression [3]. Increasing evi-
published [63]. dence shows that damage to tubular epithelial cells (TEC) has
Increasing evidence suggests that heritability of kidney func- a central role in promoting CKD progression in tubulointerstitial
tion exceeds that of monogenic Mendelian traits [64], and that diseases [85, 86]. Unlike progenitor cells, TEC are terminally dif-
the genetic make-up of CKD is more complex than previously ferentiated cells incapable of regeneration [85]. Tubulointersti-
thought. Genome-wide association studies are currently used to tial fibrosis and CKD are triggered by injury that in tubular cells
illuminate the genetic underpinnings of complex human char- promotes cell hypertrophy via polyploidization [85, 86]. Polyploid
acteristics, such as CKD. High-frequency and low effect-size vari- cells can turn senescent and drive CKD progression over time
ants in APOL1, UMOD, COL4A3 and other genes have been re- [86]. Evolutionarily, polyploidization is an adaptive mechanism
ported to increase the risk of developing kidney diseases and that allows the rapid increase of DNA content in response to
CKD [64, 65]. The combination of multiple variants in polygenic an injury, without undergoing cell division [87]. Genetic or drug-
risk scores or genome-wide polygenic scores [66, 67] and their induced defects in the DNA damage response can trigger poly-
clinical utility in identifying individuals with a high genetic pre- ploidization [88–95]. In children, mutations in DNA repair genes
disposition for CKD and in optimizing therapeutic and preven- such as FAN1 and ERCC1 [89–91] drive tubulointerstitial fibro-
tive measures is an additional active area of research [64, 68]. sis and CKD with a pathology picture of karyomegalic nephritis,
characterized by massive tubulointerstitial fibrosis and the for-
mation of enlarged nuclei in the kidneys and other tissues [89,
90, 92]. These patients experience proximal tubular dysfunction,
MECHANISMS OF CKD PROGRESSION IN
often manifested as Fanconi’s syndrome, leading to progressive
CHILDREN
kidney impairment at a young age [90]. This condition is also ob-
The mechanisms underlying CKD progression are multifactorial served in CKD secondary to ifosfamide [94] or other drugs used
and only partially understood [1]. The still low disease aware- to treat pediatric tumors [95] as well as viruses integrating into
ness further contributes to a general lack of effort in identi- the genome [96, 97]. Similar to genetic mutations, these insults
fying the causes behind its progression [1, 7]. The scenario is can affect the ability of the DNA to repair. Studies conducted be-
particularly complex in children and young adults where CKD tween 1980 and 2010 reported that CKD affects up to 30% of chil-
results mainly from hereditary disorders, birth defects or ag- dren treated with ifosfamide and is dose-dependent [98–104].
gressive treatments causing AKI (e.g. use of chemotherapeutic The scarcity of more recent data on this subject urgently calls for
drugs). The lack of uniformity in the use and timing of nephro- data renewal due to the increased survival rates after childhood
protective therapy (e.g. antiproteinuric drugs) can represent ad- cancer [105] and the growing use of ifosfamide in children [106].
ditional influencing factors. This is even more relevant when considering that ifosfamide,
Kidney is a slowly proliferating organ with a limited capacity like cisplatin and other chemotherapy drugs, can cause AKI [104,
for regeneration. During nephrogenesis and fetal development, 107] which was recognized as an important risk factor for CKD
progenitor stem cells give rise to all the different portions of the only recently [108]. Due to technical limitations in defining AKI
nephron [69]. Termination of nephrogenesis around the 34th– in children, pediatric AKI is still largely underdiagnosed. Despite
36th gestational week in humans marks the end of new nephron this, it was found to be common in pediatric intensive care units
endowment [70]. Premature and LBW babies frequently display with an incidence that spans from 10% to 35% of the admitted
incomplete kidney development and low nephron endowment children [109].
L. Cirillo et al. 5

Etiology Disease Mechanisms Available treatments

Toxic (chemotherapeutics,
antibiotics, NSAIDs) Polyploidy (including
Stop/avoid insult,
Glomerulonephritis AKI karyomegalic nephritis,
supportive measures, dialysis
Ischemia (dehydration, TEC senescence)
etc), obstruction

Polyploidy (including
Toxic (chemotherapeutics) Tubulointerstitial Stop/avoid insult, steroids,
karyomegalic nephritis,
Immunologic diseases supportive measures, dialysis

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


TEC senescence)

Genetic
Environmental factors Low nephron Reduction of nephron overload
CAKUT
(nutritional deficit in endowment (RAS blockers, SGLT2-inhibitors)
pregnancy, etc.)

Tubulointerstitial
Genetic Ciliopathies Supportive measures, dialysis
structural abnormalities

Glomerular polyploidy,
Genetic Supportive measures,
Glomerulopathies structural/functional
Immunologic immunosuppressors, dialysis
abnormalities

Figure 3: Mechanisms of CKD progression in children. Scheme summarizing the main mechanisms of pediatric CKD progression and available treatments according
to the etiology of CKD. NSAIDs, non-steroidal anti-inflammatory drugs; TEC, tubular epithelial cell; RAS, renin–angiotensin system.

Collectively, chemotherapy and tubulointerstitial damage in CKD and in CKD progression are still open questions. Final
secondary to nephrotoxic drugs, AKI and congenital conditions adult height in CKD pediatric patients is significantly reduced
can cause CKD in children [95] via TEC dysfunction suggesting compared with the healthy population [115]. All these aspects
that TEC may have a more prominent role in many different contribute to creating a gap between children and adolescents
forms of CKD than previously thought, especially in children affected by CKD and their peers, influencing the emotional, psy-
(Fig. 3). chological and social state of these patients [116]. In this view,
CKD should be considered as a “social” disease. Along with other
different disease manifestations, growth impairment severely
impacts on children’s quality of life [116]. In the CKD popula-
KIDNEY FUNCTION AND GROWTH IN CKD
tion, growth is influenced by nutrition more than the growth
PATIENTS: IS NUTRITION THE KEY? hormone–IGF-I axis [3, 110]. Patients frequently receive a re-
CKD is the result of the imbalance between the functional ca- duced intake of nutrients due to the limits imposed by CKD and
pacity of the kidney and the metabolic needs of the body. A pe- by restrictive “renal diet” [110, 117], which lead to an inadequate
culiar feature of the pediatric population is that this equation energy reserve with respect to the body requests. Drugs, loss
is unstable by definition. In growing children metabolic require- of appetite due to increased anorectic hormones and taste al-
ments substantially increase with time, while at the same time terations further contribute to poor nutrition [112, 118]. On the
in progressive CKD the kidney’s capacity to handle metabolic other hand, patients experience altered absorption of nutrients
load declines. From a clinical perspective, this mismatch can due to increased uremic toxins and bowel inflammation [119,
result in growth failure [110, 111]. The degree of growth im- 120]. For these reasons nutritional plans should be tailored to the
pairment increases as GFR declines [3, 112] and is linked to patient’s needs: age, gender, race, nutritional and growth param-
the other CKD features: anemia, metabolic acidosis, electrolytes eters, degree of physical activity, cause of CKD (i.e. presence of
anomalies, mineral-bone disorders, sexual hormones dysregu- particular electrolyte imbalance, presence of residual diuresis)
lation and malnutrition [112]. are relevant [110, 117]. The 2009 KDOQI Clinical Practice Guide-
In patients with CKD, different compensatory mechanisms line for Nutrition in Children with CKD and The Clinical Practice
are established to offset progressive loss of nephron mass. Stud- Recommendations from the Pediatric Renal Nutrition Task Force
ies in preterm and LBW infants suggest that hyperfiltration of published in 2019 suggested that the initial prescription for pro-
remaining nephrons is a key adaptive mechanism to support tein intake should be at the upper end in patient with CKD to
residual kidney function and to some extent growth [113, 114]. support growth and modulated based on urea levels and growth
Unfortunately, the tradeoff of these strategies is progressive CKD [118, 121]. To this end, the proposal to revise the use of protein
development [113]. Whether poor growth is merely a conse- restriction recently came to the stage. Recommendations on a
quence of CKD or even represents itself a factor promoting pro- low protein diet in the adult population were based on only few
gression, which is the cost-to-benefit ratio of pursuing growth in studies with weak evidence of actual effects on slowing the CKD
children with CKD and which is the role of nutrition in growth, progression [122]. According to this, it may be more important
6 Chronic kidney disease in children

Table 1: Pipeline clinical trials in pediatric CKD patients.

Clinical target Mechanism Drug Trial phase Trial identifier

Bone metabolism Calcium-sensing receptor agonist Cinacalcet III NCT02138838


Bone metabolism Calcium-sensing receptor agonist Cinacalcet III NCT01290029
Bone metabolism Calcium-sensing receptor agonist Cinacalcet II NCT01439867
Bone metabolism Calcium-sensing receptor agonist Cinacalcet III NCT02341417
Bone metabolism Calcium-sensing receptor agonist Etelcalcetide III NCT03633708
Bone metabolism Calcium-sensing receptor agonist Etelcalcetide I NCT02833857
Bone metabolism Calcium-sensing receptor agonist Etelcalcetide III NCT03969329

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


Anemia HIF2 inhibitor Vadadustat III NCT05082571
Anemia HIF2 inhibitor Vadadustat III NCT05082584
Anemia HIF2 inhibitor Roxadustat III NCT04925011
Hypertension MRAs Finerenone III NCT05196035
Hypertension MRAs Finerenone III NCT05457283
Bone metabolism Phosphate binder Lanthanum Carbonate II NCT01696279
Hyperkalemia Potassium binder Patiromer II NCT03087058
Inflammation Triterpenoid Bardoxolone III NCT03749447

to take into account the protein kind rather than the amount, thropoietin. They also seem to improve the absorption and use
as not all proteins produce the same amount of acids to be neu- of iron from food. Roxadustat is currently being tested in a clini-
tralized [122]. Given the issue of increased risk of growth impair- cal trial in pediatric CKD patients (NCT04925011) [137]. Although
ment, such reevaluation would have a great impact on the clin- the results are not yet available, these new drugs will constitute a
ical management of pediatric CKD patients. further tool to address resistance to erythropoiesis-stimulating
Enteral nutrition is recommended to support and improve agents in children. However, long-term safety still remains to be
the nutritional status of patients with low oral caloric intake or assessed.
in patients without weight improvement despite the optimiza- In children with CKD, the treatment of calcium/phosphorus
tion of the nutritional scheme [123, 124]. The first 6 months of life axis dysfunction is essential as it markedly affects growth. The
are critical for growth and can be particularly affected by mal- constitutive activation of the parathyroid hormone (PTH; i.e. sec-
nutrition requiring a more aggressive nutritional approach [112, ondary hyperparathyroidism) already occurs in the intermedi-
123, 124]. ate stages of CKD [138, 139]. Therefore, the timing of action is
The role of a plant-based diet in the management of CKD has narrow as the lost growth potential of first years is not recov-
been consolidating in recent years [125, 126]. Interventional tri- erable [140]. Calcimimetics are a class of drugs that lower the
als in adults have shown benefits in controlling metabolic acido- threshold for calcium-sensing receptors’ activation by extracel-
sis and in slowing CKD progression. Pleiotropic benefits on blood lular calcium ions, thus reducing PTH release from parathyroid
pressure, intestinal permeability and gut dysbiosis as well as re- cells [141]. These drugs are already in use in adult CKD patients
ducing the medications burden have been suggested [119, 125– on dialysis. Recently, a small number of sponsored trials has
127]. Although promising, studies on the ability of vegetarian di- been completed using cinacalcet, available for children over 3
ets to satisfy nutritional needs and optimize growth in pediatric years old on dialysis with hyperparathyroidism not controlled
patients with CKD are lacking. with standard-of-care therapy. First results showed the reduc-
In conclusion, nutrition could represent a tool for slowing tion of PTH level in up to 57.1% of enrolled patients [142]. Etel-
down CKD progression, reducing the use of drugs and improving calcetide is under study in a phase III trial (NCT03633708) [143].
growth in pediatric patients with CKD. However, a personalized Additional drugs acting on calcium metabolism have been pro-
approach should be tailored to each patient to ensure the appro- posed to enter into use for the pediatric population in the next
priate balance among all clinical needs. few years [139].
Mineralocorticoid receptor antagonists (MRA) are used for
treating low-renin or refractory hypertension [144, 145]. Previ-
ous MRA antagonists, spironolactone and eplerenone, did not
NEW THERAPEUTIC PERSPECTIVES FOR
receive wider use in CKD patients mainly for safety concerns
PEDIATRIC CKD
related to hyperkalemia [146] and for sex hormone–related ad-
Given the burden of CKD, new therapies allowing better clini- verse events due to affinity for progesterone and androgen re-
cal management and slowing disease progression are needed. ceptors [145]. Recently, a new highly selective, non-steroidal
The most recent years have been characterized by excitement MRA, finerenone, has been shown to be effective in improv-
for new therapeutic options that have just entered clinical prac- ing renal outcome in patients with diabetic CKD in two trials:
tice for the adult patients. Some of them will be tested in pedi- FIDELIO-DKD [147] and FIGARO-DKD [148]. These trials enrolled
atric patients (Table 1) [128]. mainly albuminuric patients, therefore data on the efficacy in
New therapeutic options became available for CKD-related non-albuminuric patients with diabetic and nondiabetic kidney
anemia. Large trials using hypoxia-inducible factor 2 prolyl disease are still missing. The FIND-CKD study (NCT05047263)
hydroxylase inhibitors (HIF2-PHIs; roxadustat, vadadustat and investigating finerenone in adult nondiabetic CKD is ongoing
daprodustat) were completed in adult patients with positive re- [149]. Interestingly, finerenone is currently being tested in two
sults [129–136]. These compounds act by slowing the degrada- phase III open-label trials (FIONA, NCT05196035; FIONA OLE,
tion of HIFs, thus enhancing the production of endogenous ery- NCT05457283) for pediatric CKD patients [149–151].
L. Cirillo et al. 7

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were FUNDING


originally designed for diabetic patients with CKD and then
This study received funding by the European Research Council
were found to be protective even in the adult population with
(ERC) under the European Union’s Horizon 2020 research and in-
nondiabetic CKD [152]. They reduced the risk of kidney disease
novation program (grant agreement no. 101019891) to P.R.
progression up to 37% (relative risk 0.63, 95% confidence in-
terval 0.58–0.69) and improved kidney and cardiovascular out-
comes, making them a game-changer historically comparable DATA AVAILABILITY STATEMENT
only to renin–angiotensin system inhibitors [153]. The long-term
protective mechanisms are still being elucidated, however it is No new data were generated or analysed in support of this
thought that in the kidney they may act mainly through the research.

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


inhibition of the tubuloglomerular feedback, which is dysfunc-
tional in CKD, reducing hyperfiltration [154, 155]. Other proposed
mechanisms are the systemic metabolic reset linked to nutrient
CONFLICT OF INTEREST STATEMENT
deprivation signaling with its cytoprotective effects and reduc- P.R. is member of the CKJ editorial board. The other authors have
tion of mitochondrial oxidative stress in proximal tubular cells no conflict of interest.
[155]. Interestingly, a recent analysis showed that SGLT2i can
provide a substantial reduction in costs related to CKD, mainly
driven by the reduction in the outcomes and by the cardio- and
nephroprotective effects [156–159]. Furthermore, the issue of REFERENCES
cost-effectiveness is especially relevant in children. Recent pilot 1. Romagnani P, Remuzzi G, Glassock R et al. Chronic kidney
studies suggested that SGLT2i are effective in reducing protein- disease. Nat Rev Dis Primers 2017;3:17088. https://doi.org/10.
uria in children with CKD [160, 161]. Despite these big premises, 1038/nrdp.2017.88.
up to now no trials have been registered for pediatric CKD pa- 2. Jager KJ, Kovesdy C, Langham R et al. A single number
tients [152]. for advocacy and communication-worldwide more than
In recent years new drugs to slow CKD progression have 850 million individuals have kidney diseases. Kidney Int
entered into the nephrologist’s clinical practice. However the 2019;96:1048–50. https://doi.org/10.1016/j.kint.2019.07.012.
efforts for bringing them into daily practice probably should 3. Becherucci F, Roperto RM, Materassi M et al. Chronic kidney
be increased by pediatric nephrologists, considering the lower disease in children. Clin Kidney J 2016;9:583–91. https://doi.
number of clinical trials registered for CKD when compared org/10.1093/ckj/sfw047.
with that of other conditions such as heart failure and the low 4. Annual reports ESPN/ERA Registry [Internet] [cited 2022
number of trials resulting in effective publication [162]. Dec 21]. Available from: https://espn-reg.org/index.jsp?p=
pua (21 December 2022, last date accessed).
5. Annual Data Report US Department of Health and Human
CONCLUSIONS Services, USRDS 2022 Annual Data Report [Internet] [cited
2022 Dec 21]. Available from: https://adr.usrds.org/ (21 De-
The heterogeneity of causes and the lack of complete under- cember 2022, last date accessed).
standing of mechanisms underlying CKD in children are re- 6. Stevens PE, Levin A; Kidney Disease: Improving Global
flected in the absence of effective treatments to slow CKD dis- Outcomes Chronic Kidney Disease Guideline Development
ease progression and prolong patient survival, with profound Work Group Members. Evaluation and management of
implications for morbidity and mortality. Given the economi- chronic kidney disease: synopsis of the Kidney Disease:
cal and organizational concerns related to CKD, any intervention Improving Global Outcomes 2012 clinical practice guide-
potentially leading to preventing its progression toward kidney line. Ann Intern Med 2013;158:825–30. https://doi.org/10.
failure is crucial and would be required to appropriately allo- 7326/0003-4819-158-11-201306040-00007.
cate resources [7]. The main step on this path is the identifi- 7. Harambat J, Madden I. What is the true burden of
cation and correct disease classification, which is still difficult chronic kidney disease in children worldwide? Pedi-
given the peculiarities of pediatric patients. This can only be atr Nephrol 2023;38:1389–93. http://dx.doi.org/10.1007/
successfully achieved by acting on multiple fronts: (i) promoting s00467-022-05816-7.
disease awareness ensuring a correct and timely identification 8. Levey AS, Eckardt K-U, Dorman NM et al. Nomenclature
of pediatric patients with CKD; (ii) incorporating cutting-edge for kidney function and disease: report of a Kidney Dis-
technologies in diagnostic pathways; (iii) understanding disease ease: Improving Global Outcomes (KDIGO) Consensus Con-
progression mechanisms; (iv) balancing out the need to promote ference. Kidney Int 2020;97:1117–29. https://doi.org/10.1016/
growth and keep CKD under control; and (v) incorporating newly j.kint.2020.02.010.
available treatments for CKD resulting from either translation of 9. Schwartz GJ, Abraham AG, Furth SL et al. Optimizing
results from clinical trials in adults or as directly designed for iohexol plasma disappearance curves to measure the
the pediatric CKD population. Only by synergistically combining glomerular filtration rate in children with chronic kidney
these fronts together will effectively acting on preventing CKD disease. Kidney Int 2010;77:65–71. https://doi.org/10.1038/ki.
and its devastating consequences in the pediatric population be- 2009.398.
come routine clinical practice. 10. Dostbil Z, Pembegül N, Küçüköner M et al. Comparison
of split renal function measured by 99mTc-DTPA, 99mTc-
MAG3 and 99mTc-DMSA renal scintigraphies in paediatric
age groups. Clin Rev Opin 2011;3:20–5.
ACKNOWLEDGEMENTS 11. Ritchie G, Wilkinson AG, Prescott RJ. Comparison of dif-
L.C., P.R. and F.B. are members of the European Reference Net- ferential renal function using technetium-99m mercap-
work for Rare Kidney Diseases (ERKNet). toacetyltriglycine (MAG3) and technetium-99m dimercap-
8 Chronic kidney disease in children

tosuccinic acid (DMSA) renography in a paediatric popula- 27. Filler G, Ferris M, Gattineni J. Assessment of kidney func-
tion. Pediatr Radiol 2008;38:857–62. https://doi.org/10.1007/ tion in children, adolescents, and young adults. In: Emma
s00247-008-0908-8. F, Goldstein S, Bagga A, Bates CM, Shroff R (eds.), Pediatric
12. Vart P, Grams ME. Measuring and assessing kidney func- Nephrology. Berlin, Heidelberg: Springer, 2021, 1–27. https:
tion. Semin Nephrol 2016;36:262–72. https://doi.org/10.1016/ //doi.org/10.1007/978-3-642-27843-3_87-1.
j.semnephrol.2016.05.003. 28. Bariciak E, Yasin A, Harrold J et al. Preliminary reference in-
13. Schwartz GJ, Muñoz A, Schneider MF et al. New equations tervals for cystatin C and beta-trace protein in preterm and
to estimate GFR in children with CKD. J Am Soc Nephrol term neonates. Clin Biochem 2011;44:1156–9. https://doi.org/
2009;20:629–37. https://doi.org/10.1681/ASN.2008030287. 10.1016/j.clinbiochem.2011.06.987.
14. Gao A, Cachat F, Faouzi M et al. Comparison of the 29. Smeets NJL, IntHout J, van der Burgh MJP et al. Matura-

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


glomerular filtration rate in children by the new revised tion of GFR in term-born neonates: an individual partici-
Schwartz formula and a new generalized formula. Kidney pant data meta-analysis. J Am Soc Nephrol 2022;33:1277–92.
Int 2013;83:524–30. http://dx.doi.org/10.1038/ki.2012.388. https://doi.org/10.1681/ASN.2021101326.
15. Adebayo OC, Nkoy AB, van den Heuvel LP et al. Glomerular 30. Mohr Lytsen R, Taageby Nielsen S, Kongsgaard Hansen
hyperfiltration: part 2—clinical significance in chil- M et al. Markers of kidney function in early childhood
dren. Pediatr Nephrol 2022. http://dx.doi.org/10.1007/ and association with maternal comorbidity. JAMA
s00467-022-05826-5. Netw Open 2022;5:e2243146. https://doi.org/10.1001/
16. Pierce CB, Muñoz A, Ng DK et al. Age- and sex-dependent jamanetworkopen.2022.43146.
clinical equations to estimate glomerular filtration rates in 31. Stojanović V, Barišić N, Milanović B et al. Acute kidney in-
children and young adults with chronic kidney disease. Kid- jury in preterm infants admitted to a neonatal intensive
ney Int 2021;99:948–56. https://doi.org/10.1016/j.kint.2020. care unit. Pediatr Nephrol 2014;29:2213–20. https://doi.org/
10.047. 10.1007/s00467-014-2837-0.
17. Ng DK, Schwartz GJ, Schneider MF et al. Combination of 32. Jetton JG, Boohaker LJ, Sethi SK et al. Incidence and out-
pediatric and adult formulas yield valid glomerular filtra- comes of neonatal acute kidney injury (AWAKEN): a mul-
tion rate estimates in young adults with a history of pedi- ticentre, multinational, observational cohort study. Lancet
atric chronic kidney disease. Kidney Int 2018;94:170–7. https: Child Adolesc Health 2017;1:184–94.
//doi.org/10.1016/j.kint.2018.01.034. 33. Hingorani S, Schmicker R, Ahmad KA et al. Prevalence and
18. Pottel H, Björk J, Delanaye P et al. Evaluation of the risk factors for kidney disease and elevated BP in 2-year-old
creatinine-based chronic kidney disease in children (under children born extremely premature. Clin J Am Soc Nephrol
25 years) equation in healthy children and adoles- 2022;17:1129–38. https://doi.org/10.2215/CJN.15011121.
cents. Pediatr Nephrol 2022;37:2213–6. https://doi.org/10. 34. Goldstein SL. Pediatric acute kidney injury—the time for
1007/s00467-022-05429-0. nihilism is over. Front Pediatr 2020;8:16. http://dx.doi.org/10.
19. In ‘t Woud SG, Westland R, Feitz WFJ et al. Clinical man- 3389/fped.2020.00016.
agement of children with a congenital solitary functioning 35. Renganathan A, Warner BB, Tarr PI et al. The progres-
kidney: overview and recommendations. Eur Urol Open Sci sion of serum cystatin C concentrations within the first
2021;25:11–20. https://doi.org/10.1016/j.euros.2021.01.003. month of life after preterm birth-a worldwide systematic
20. Obrycki Ł, Sarnecki J, Lichosik M et al. Kidney length nor- review. Pediatr Nephrol 2021;36:1709–18. https://doi.org/10.
mative values in children aged 0-19 years - a multicen- 1007/s00467-020-04543-1.
ter study. Pediatr Nephrol 2022;37:1075–85. https://doi.org/ 36. van Eerde AM, Krediet CTP, Rookmaaker MB et al. Pre-
10.1007/s00467-021-05303-5. pregnancy advice in chronic kidney disease: do not for-
21. Wühl E, van Stralen KJ, Verrina E et al. Timing and outcome get genetic counseling. Kidney Int 2016;90:905–6. https://doi.
of renal replacement therapy in patients with congenital org/10.1016/j.kint.2016.05.035.
malformations of the kidney and urinary tract. Clin J Am Soc 37. Rasouly HM, Groopman EE, Heyman-Kantor R et al. The
Nephrol 2013;8:67–74. https://doi.org/10.2215/CJN.03310412. burden of candidate pathogenic variants for kidney and
22. Sanna-Cherchi S, Ravani P, Corbani V et al. Renal outcome genitourinary disorders emerging from exome sequenc-
in patients with congenital anomalies of the kidney and ing. Ann Intern Med 2019;170:11–21. https://doi.org/10.7326/
urinary tract. Kidney Int 2009;76:528–33. https://doi.org/10. M18-1241.
1038/ki.2009.220. 38. KDIGO Conference Participants. Genetics in chronic kid-
23. Caroli A, Remuzzi A, Lerman LO. Basic principles and new ney disease: conclusions from a Kidney Disease: Improv-
advances in kidney imaging. Kidney Int 2021;100:1001–11. ing Global Outcomes (KDIGO) Controversies Conference.
https://doi.org/10.1016/j.kint.2021.04.032. Kidney Int 2022;101:1126–41. https://doi.org/10.1016/j.kint.
24. Charlton JR, Xu Y, Parvin N et al. Image analysis techniques 2022.03.019.
to map pyramids, pyramid structure, glomerular distribu- 39. Knoers N, Antignac C, Bergmann C et al. Genetic testing in
tion, and pathology in the intact human kidney from 3- the diagnosis of chronic kidney disease: recommendations
D MRI. Am J Physiol Renal Physiol 2021;321:F293–304. https: for clinical practice. Nephrol Dial Transplant 2022;37:239–54.
//doi.org/10.1152/ajprenal.00130.2021. https://doi.org/10.1093/ndt/gfab218.
25. Baldelomar EJ, Charlton JR, Beeman SC et al. Measuring rat 40. Groopman EE, Povysil G, Goldstein DB et al. Rare ge-
kidney glomerular number and size in vivo with MRI. Am netic causes of complex kidney and urological diseases.
J Physiol Renal Physiol 2018;314:F399–406. https://doi.org/10. Nat Rev Nephrol 2020;16:641–56. https://doi.org/10.1038/
1152/ajprenal.00399.2017. s41581-020-0325-2.
26. Perl AJ, Schuh MP, Kopan R. Regulation of nephron 41. Boenink R, Astley ME, Huijben JA et al. The ERA Reg-
progenitor cell lifespan and nephron endowment. Nat istry Annual Report 2019: summary and age comparisons.
Rev Nephrol 2022;18:683–95. https://doi.org/10.1038/ Clin Kidney J 2022;15:452–72. https://doi.org/10.1093/ckj/
s41581-022-00620-w. sfab273.
L. Cirillo et al. 9

42. Bonthuis M, Vidal E, Bjerre A et al. Ten-year trends in 59. Mallett A, Fowles LF, McGaughran J et al. A multidis-
epidemiology and outcomes of pediatric kidney replace- ciplinary renal genetics clinic improves patient diagno-
ment therapy in Europe: data from the ESPN/ERA-EDTA sis. Med J Aust 2016;204:58–9. https://doi.org/10.5694/mja15.
Registry. Pediatr Nephrol 2021;36:2337–48. https://doi.org/10. 01157.
1007/s00467-021-04928-w. 60. Alkanderi S, Yates LM, Johnson SA et al. Lessons learned
43. Vivante A, Hildebrandt F. Exploring the genetic basis from a multidisciplinary renal genetics clinic. QJM
of early-onset chronic kidney disease. Nat Rev Nephrol 2017;110:453–7. https://doi.org/10.1093/qjmed/hcx030.
2016;12:133–46. 61. Jayasinghe K, Wu Y, Stark Z et al. Cost-effectiveness of tar-
44. Mann N, Braun DA, Amann K et al. Whole-exome se- geted exome analysis as a diagnostic test in glomerular
quencing enables a precision medicine approach for kid- diseases. Kidney Int Rep 2021;6:2850–61. https://doi.org/10.

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


ney transplant recipients. J Am Soc Nephrol 2019;30:201–15. 1016/j.ekir.2021.08.028.
https://doi.org/10.1681/ASN.2018060575. 62. Becherucci F, Landini S, Palazzo V et al. A clinical workflow
45. Cocchi E, Nestor JG, Gharavi AG. Clinical genetic screening for cost-saving high-rate diagnosis of genetic kidney dis-
in adult patients with kidney disease. Clin J Am Soc Nephrol eases. J Am Soc Nephrol 2023;34:706–20. http://dx.doi.org/10.
2020;15:1497–510. https://doi.org/10.2215/CJN.15141219. 1681/asn.0000000000000076.
46. Knoers NVAM, Renkema KY. The genomic landscape 63. 100,000 Genomes Project Pilot Investigators, Smedley D,
of CAKUT; you gain some, you lose some. Kidney Int Smith KR et al. 100,000 genomes pilot on rare-disease di-
2019;96:267–9. https://doi.org/10.1016/j.kint.2019.03.017. agnosis in health care - preliminary report. N Engl J Med
47. Torra R, Furlano M, Ortiz A et al. Genetic kidney diseases 2021;385:1868–80.
as an underrecognized cause of chronic kidney disease: 64. Tin A, Köttgen A. Genome-wide association studies of CKD
the key role of international registry reports. Clin Kidney J and related traits. Clin J Am Soc Nephrol 2020;15:1643–56.
2021;14:1879–85. https://doi.org/10.1093/ckj/sfab056. https://doi.org/10.2215/CJN.00020120.
48. Connaughton DM, Kennedy C, Shril S et al. Monogenic 65. Sanchez-Rodriguez E, Southard CT, Kiryluk K. GWAS-based
causes of chronic kidney disease in adults. Kidney Int discoveries in IgA nephropathy, membranous nephropa-
2019;95:914–28. https://doi.org/10.1016/j.kint.2018.10.031. thy, and steroid-sensitive nephrotic syndrome. Clin J
49. Jayasinghe K, Stark Z, Kerr PG et al. Clinical impact of ge- Am Soc Nephrol 2021;16:458–66. https://doi.org/10.2215/CJN.
nomic testing in patients with suspected monogenic kid- 14031119.
ney disease. Genet Med 2021;23:183–91. https://doi.org/10. 66. Sugrue LP, Desikan RS. What are polygenic scores and why
1038/s41436-020-00963-4. are they important? JAMA 2019;321:1820–1. https://doi.org/
50. Pinto E Vairo F, Prochnow C, Kemppainen JL et al. Ge- 10.1001/jama.2019.3893.
nomics integration into nephrology practice. Kidney Med 67. Khera AV, Chaffin M, Aragam KG et al. Genome-wide
2021;3:785–98. https://doi.org/10.1016/j.xkme.2021.04.014. polygenic scores for common diseases identify in-
51. Schrezenmeier E, Kremerskothen E, Halleck F et al. dividuals with risk equivalent to monogenic muta-
The underestimated burden of monogenic kidney tions. Nat Genet 2018;50:1219–24. https://doi.org/10.1038/
disease in adults waitlisted for kidney transplanta- s41588-018-0183-z.
tion. Genet Med 2021;23:1219–24. https://doi.org/10.1038/ 68. Khan A, Turchin MC, Patki A et al. Genome-wide poly-
s41436-021-01127-8. genic score to predict chronic kidney disease across an-
52. Groopman EE, Marasa M, Cameron-Christie S et al. Di- cestries. Nat Med 2022;28:1412–20. https://doi.org/10.1038/
agnostic utility of exome sequencing for kidney dis- s41591-022-01869-1.
ease. N Engl J Med 2019;380:142–51. https://doi.org/10.1056/ 69. Barker N, Rookmaaker MB, Kujala P et al. Lgr5(+ve)
NEJMoa1806891. stem/progenitor cells contribute to nephron formation
53. Stokman MF, Renkema KY, Giles RH et al. The expanding during kidney development. Cell Rep 2012;2:540–52. https:
phenotypic spectra of kidney diseases: insights from ge- //doi.org/10.1016/j.celrep.2012.08.018.
netic studies. Nat Rev Nephrol 2016;12:472–83. 70. Blake J, Rosenblum ND. Renal branching morphogenesis:
54. Hays T, Groopman EE, Gharavi AG. Genetic testing for kid- morphogenetic and signaling mechanisms. Semin Cell Dev
ney disease of unknown etiology. Kidney Int 2020;98:590– Biol 2014;36:2–12.
600. https://doi.org/10.1016/j.kint.2020.03.031. 71. Low Birth Weight and Nephron Number Working Group.
55. Cirillo L, Becherucci F. Genetic testing in nephrology: The impact of kidney development on the life course:
show your pedigree! Kidney360 2022;3:2148–52. https:// a consensus document for action. Nephron 2017;136:3–49.
doi.org/10.34067/KID.0002732022. https://doi.org/10.34067/ https://doi.org/10.1159/000457967.
KID.0002732022. 72. Hirano D, Ishikura K, Uemura O et al. Association between
56. Thomas CP, Freese ME, Ounda A et al. Initial experience low birth weight and childhood-onset chronic kidney dis-
from a renal genetics clinic demonstrates a distinct role ease in Japan: a combined analysis of a nationwide survey
in patient management. Genet Med 2020;22:1025–35. https: for paediatric chronic kidney disease and the National Vital
//doi.org/10.1038/s41436-020-0772-y. Statistics Report. Nephrol Dial Transplant 2016;31:1895–900.
57. Tanudisastro HA, Holman K, Ho G et al. Australia and New https://doi.org/10.1093/ndt/gfv425.
Zealand renal gene panel testing in routine clinical prac- 73. Sergio M, Galarreta CI, Thornhill BA et al. The fate of
tice of 542 families. NPJ Genom Med 2021;6:20. https://doi. nephrons in congenital obstructive nephropathy: adult re-
org/10.1038/s41525-021-00184-x. covery is limited by nephron number despite early release
58. Pode-Shakked B, Ben-Moshe Y, Barel O et al. A multi- of obstruction. J Urol 2015;194:1463–72. https://doi.org/10.
disciplinary nephrogenetic referral clinic for children 1016/j.juro.2015.04.078.
and adults-diagnostic achievements and insights. Pe- 74. Rosenblum S, Pal A, Reidy K. Renal development in the
diatr Nephrol 2022;37:1623–46. https://doi.org/10.1007/ fetus and premature infant. Semin Fetal Neonatal Med
s00467-021-05374-4. 2017;22:58–66.
10 Chronic kidney disease in children

75. Stark K, Vainio S, Vassileva G et al. Epithelial transformation in patients. J Exp Med 2021;218:e20200622. http://dx.doi.org/
of metanephric mesenchyme in the developing kidney reg- 10.1084/jem.20200622.
ulated by Wnt-4. Nature 1994;372:679–83. https://doi.org/10. 91. Weeda G, Donker I, de Wit J et al. Disruption of
1038/372679a0. mouse ERCC1 results in a novel repair syndrome
76. Kanda S, Tanigawa S, Ohmori T et al. Sall1 maintains with growth failure, nuclear abnormalities and senes-
nephron progenitors and nascent nephrons by acting cence. Curr Biol 1997;7:427–39. https://doi.org/10.1016/
as both an activator and a repressor. J Am Soc Nephrol S0960-9822(06)00190-4.
2014;25:2584–95. https://doi.org/10.1681/ASN.2013080896. 92. De Chiara L, Romagnani P. Polyploid tubular cells and
77. Becherucci F, Lazzeri E, Lasagni L et al. Renal pro- chronic kidney disease. Kidney Int 2022;102:959–61.
genitors and childhood: from development to disor- https://doi.org/10.1016/j.kint.2022.08.017.

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


ders. Pediatr Nephrol 2014;29:711–9. https://doi.org/10.1007/ 93. Airik M, Phua YL, Huynh AB et al. Persistent DNA damage
s00467-013-2686-2. underlies tubular cell polyploidization and progression to
78. Angelotti ML, Ronconi E, Ballerini L et al. Characterization chronic kidney disease in kidneys deficient in the DNA re-
of renal progenitors committed toward tubular lineage and pair protein FAN1. Kidney Int 2022;102:1042–56. https://doi.
their regenerative potential in renal tubular injury. Stem org/10.1016/j.kint.2022.07.003.
Cells 2012;30:1714–25. https://doi.org/10.1002/stem.1130. 94. McCulloch T, Prayle A, Lunn A et al. Karyomegalic-
79. Forbes MS, Thornhill BA, Galarreta CI et al. Chronic uni- like nephropathy, Ewing’s sarcoma and ifosfamide ther-
lateral ureteral obstruction in the neonatal mouse de- apy. Pediatr Nephrol 2011;26:1163–6. https://doi.org/10.1007/
lays maturation of both kidneys and leads to late for- s00467-011-1815-z.
mation of atubular glomeruli. Am J Physiol Renal Physiol 95. De Chiara L, Lugli G, Villa G et al. Molecular mechanisms
2013;305:F1736–46. https://doi.org/10.1152/ajprenal.00152. and biomarkers associated with chemotherapy-induced
2013. AKI. Int J Mol Sci 2022;23:2638. http://dx.doi.org/10.3390/
80. Arcolino FO, Zia S, Held K et al. Urine of preterm neonates ijms23052638.
as a novel source of kidney progenitor cells. J Am Soc Nephrol 96. Chen Y, Chen Y, Fu J et al. Tubular-specific expression of HIV
2016;27:2762–70. https://doi.org/10.1681/ASN.2015060664. protein Vpr leads to severe tubulointerstitial damage ac-
81. Suzuki T, Kimura M, Asano M et al. Role of atrophic tubules companied by progressive fibrosis and cystic development.
in development of interstitial fibrosis in microembolism- Kidney Int 2023;103:529–43. http://dx.doi.org/10.1016/j.kint.
induced renal failure in rat. Am J Pathol 2001;158:75–85. 2022.12.012.
https://doi.org/10.1016/S0002-9440(10)63946-6. 97. Hard GC. Critical review of renal tubule karyomegaly in
82. Chevalier RL. The proximal tubule is the primary tar- non-clinical safety evaluation studies and its significance
get of injury and progression of kidney disease: role for human risk assessment. Crit Rev Toxicol 2018;48:575–95.
of the glomerulotubular junction. Am J Physiol Renal https://doi.org/10.1080/10408444.2018.1503641.
Physiol 2016;311:F145–61. https://doi.org/10.1152/ajprenal. 98. Skinner R. Chronic ifosfamide nephrotoxicity in children.
00164.2016. Med Pediatr Oncol 2003;41:190–7. https://doi.org/10.1002/
83. Amanullah F, Malik AA, Zaidi Z. Chronic kidney disease mpo.10336.
causes and outcomes in children: perspective from a LMIC 99. Suarez A, McDowell H, Niaudet P et al. Long-term follow-
setting. PLoS One 2022;17:e0269632. https://doi.org/10.1371/ up of ifosfamide renal toxicity in children treated for ma-
journal.pone.0269632. lignant mesenchymal tumors: an International Society
84. Cerqueira DC, Soares CM, Silva VR et al. A predictive model of Pediatric Oncology report. J Clin Oncol 1991;9:2177–82.
of progression of CKD to ESRD in a predialysis pediatric in- https://doi.org/10.1200/JCO.1991.9.12.2177.
terdisciplinary program. Clin J Am Soc Nephrol 2014;9:728–35. 100. Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephro-
https://doi.org/10.2215/CJN.06630613. toxicity after ifosfamide treatment in children: a UKCCSG
85. Lazzeri E, Angelotti ML, Peired A et al. Endocycle-related Late Effects Group study. United Kingdom Children’s Can-
tubular cell hypertrophy and progenitor proliferation re- cer Study Group. Br J Cancer 2000;82:1636–45.
cover renal function after acute kidney injury. Nat Commun 101. Burk CD, Restaino I, Kaplan BS et al. Ifosfamide-induced
2018;9:1344. https://doi.org/10.1038/s41467-018-03753-4. renal tubular dysfunction and rickets in children with
86. De Chiara L, Conte C, Semeraro R et al. Tubular cell poly- Wilms tumor. J Pediatr 1990;117:331–5. https://doi.org/10.
ploidy protects from lethal acute kidney injury but pro- 1016/S0022-3476(05)80557-8.
motes consequent chronic kidney disease. Nat Commun 102. Stöhr W, Paulides M, Bielack S et al. Ifosfamide-induced
2022;13:5805. https://doi.org/10.1038/s41467-022-33110-5. nephrotoxicity in 593 sarcoma patients: a report from
87. Lazzeri E, Angelotti ML, Conte C et al. Surviving acute the Late Effects Surveillance System. Pediatr Blood Cancer
organ failure: cell polyploidization and progenitor prolif- 2007;48:447–52.
eration. Trends Mol Med 2019;25:366–81. https://doi.org/10. 103. Oberlin O, Fawaz O, Rey A et al. Long-term evaluation of
1016/j.molmed.2019.02.006. ifosfamide-related nephrotoxicity in children. J Clin Oncol
88. Airik R, Schueler M, Airik M et al. A FANCD2/FANCI- 2009;27:5350–5. https://doi.org/10.1200/JCO.2008.17.5257.
associated nuclease 1-knockout model develops karyome- 104. McMahon KR, Harel-Sterling M, Pizzi M et al. Long-
galic interstitial nephritis. J Am Soc Nephrol 2016;27:3552–9. term renal follow-up of children treated with cis-
https://doi.org/10.1681/ASN.2015101108. platin, carboplatin, or ifosfamide: a pilot study. Pe-
89. Zhou W, Otto EA, Cluckey A et al. FAN1 mutations cause diatr Nephrol 2018;33:2311–20. https://doi.org/10.1007/
karyomegalic interstitial nephritis, linking chronic kid- s00467-018-3976-5.
ney failure to defective DNA damage repair. Nat Genet 105. Yeh JM, Ward ZJ, Chaudhry A et al. Life expectancy of adult
2012;44:910–5. https://doi.org/10.1038/ng.2347. survivors of childhood cancer over 3 decades. JAMA On-
90. Apelt K, White SM, Kim HS et al. ERCC1 mutations impede col 2020;6:350–7. https://doi.org/10.1001/jamaoncol.2019.
DNA damage repair and cause liver and kidney dysfunction 5582.
L. Cirillo et al. 11

106. Carli M, Passone E, Perilongo G et al. Ifosfamide in pedi- 124. Rees L, Shaw V, Qizalbash L et al. Delivery of a nutri-
atric solid tumors. Oncology 2003;65:99–104. https://doi.org/ tional prescription by enteral tube feeding in children with
10.1159/000073369. chronic kidney disease stages 2-5 and on dialysis-clinical
107. Ensergueix G, Pallet N, Joly D et al. Ifosfamide nephro- practice recommendations from the Pediatric Renal Nutri-
toxicity in adult patients. Clin Kidney J 2020;13:660–5. tion Taskforce. Pediatr Nephrol 2021;36:187–204. https://doi.
https://doi.org/10.1093/ckj/sfz183. org/10.1007/s00467-020-04623-2.
108. Kellum JA, Romagnani P, Ashuntantang G et al. Acute kid- 125. Joshi S, Hashmi S, Shah S et al. Plant-based diets for preven-
ney injury. Nat Rev Dis Primers 2021;7:52. https://doi.org/10. tion and management of chronic kidney disease. Curr Opin
1038/s41572-021-00284-z. Nephrol Hypertens 2020;29:16. https://doi.org/10.1097/MNH.
109. Sethi SK, Bunchman T, Chakraborty R et al. Pediatric acute 0000000000000574.

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


kidney injury: new advances in the last decade. Kidney Res 126. Goraya N, Simoni J, Jo C-H et al. A comparison of treating
Clin Pract 2021;40:40–51. https://doi.org/10.23876/j.krcp.20. metabolic acidosis in CKD Stage 4 hypertensive kidney dis-
074. ease with fruits and vegetables or sodium bicarbonate. Clin
110. Silverstein DM. Growth and nutrition in pediatric chronic J Am Soc Nephrol 2013;8:371–81. http://dx.doi.org/10.2215/
kidney disease. Front Pediatr 2018;6:205. https://doi.org/10. cjn.02430312.
3389/fped.2018.00205. 127. Mocanu C-A, Simionescu TP, Mocanu AE et al. Plant-based
111. Gat-Yablonski G, Phillip M. Nutritionally-induced catch- versus animal-based low protein diets in the management
up growth. Nutrients 2015;7:517–51. https://doi.org/10.3390/ of chronic kidney disease. Nutrients 2021;13:3721. http://dx.
nu7010517. doi.org/10.3390/nu13113721.
112. Rees L, Mak RH. Nutrition and growth in children with 128. Breyer MD, Susztak K. The next generation of therapeu-
chronic kidney disease. Nat Rev Nephrol 2011;7:615–23. tics for chronic kidney disease. Nat Rev Drug Discovery
https://doi.org/10.1038/nrneph.2011.137. 2016;15:568–88. http://dx.doi.org/10.1038/nrd.2016.67.
113. Abitbol CL, Rodriguez MM. The long-term renal and 129. Tonelli M, Thadhani R. Anaemia in chronic kidney
cardiovascular consequences of prematurity. Nat Rev disease: what do new generation agents offer? Lancet
Nephrol 2012;8:265–74. https://doi.org/10.1038/nrneph. North Am Ed 2022;399:702–3. https://doi.org/10.1016/
2012.38. S0140-6736(22)00120-9.
114. Harer MW, Charlton JR, Tipple TE et al. Preterm birth and 130. Koury MJ, Haase VH. Anaemia in kidney disease:
neonatal acute kidney injury: implications on adolescent harnessing hypoxia responses for therapy. Nat Rev
and adult outcomes. J Perinatol 2020;40:1286–95. https://doi. Nephrol 2015;11:394–410. https://doi.org/10.1038/nrneph.
org/10.1038/s41372-020-0656-7. 2015.82.
115. Haffner D, Zivicnjak M. Pubertal development in children 131. Chen N, Hao C, Liu B-C et al. Roxadustat treatment for ane-
with chronic kidney disease. Pediatr Nephrol 2017;32:949–64. mia in patients undergoing long-term dialysis. N Engl J Med
https://doi.org/10.1007/s00467-016-3432-3. 2019;381:1011–22. https://doi.org/10.1056/NEJMoa1901713.
116. Assadi F. Psychological impact of chronic kidney dis- 132. Chen N, Hao C, Peng X et al. Roxadustat for anemia
ease among children and adolescents: not rare and not in patients with kidney disease not receiving dialysis.
benign. J Nephropathol 2013;2:1–3. https://doi.org/10.5812/ N Engl J Med 2019;381:1001–10. http://dx.doi.org/10.1056/
nephropathol.8968. nejmoa1813599.
117. Drube J, Wan M, Bonthuis M et al. Clinical practice rec- 133. Chertow GM, Pergola PE, Farag YMK et al. Vadadustat in
ommendations for growth hormone treatment in children patients with anemia and non-dialysis-dependent CKD.
with chronic kidney disease. Nat Rev Nephrol 2019;15:577– N Engl J Med 2021;384:1589–600. https://doi.org/10.1056/
89. https://doi.org/10.1038/s41581-019-0161-4. NEJMoa2035938.
118. Shaw V, Polderman N, Renken-Terhaerdt J et al. En- 134. Eckardt K-U, Agarwal R, Aswad A et al. Safety and effi-
ergy and protein requirements for children with CKD cacy of vadadustat for anemia in patients undergoing dial-
stages 2-5 and on dialysis-clinical practice recommenda- ysis. N Engl J Med 2021;384:1601–12. https://doi.org/10.1056/
tions from the Pediatric Renal Nutrition Taskforce. Pedi- NEJMoa2025956.
atr Nephrol 2020;35:519–31. https://doi.org/10.1007/s00467- 135. Singh AK, Carroll K, McMurray JJV et al. Daprodustat for the
019-04426-0. treatment of anemia in patients not undergoing dialysis.
119. Mafra D, Borges NA, Lindholm B et al. Food as medicine: N Engl J Med 2021;385:2313–24. http://dx.doi.org/10.1056/
targeting the uraemic phenotype in chronic kidney dis- nejmoa2113380.
ease. Nat Rev Nephrol 2021;17:153–71. https://doi.org/10. 136. Singh AK, Carroll K, Perkovic V et al. Daprodustat for
1038/s41581-020-00345-8. the treatment of anemia in patients undergoing dialysis.
120. Rysz J, Franczyk B, Ławiński J et al. The impact of CKD on N Engl J Med 2021;385:2325–35. http://dx.doi.org/10.1056/
uremic toxins and gut microbiota. Toxins 2021;13:252. http: nejmoa2113379.
//dx.doi.org/10.3390/toxins13040252. 137. Investigating the Efficacy and Safety of Roxadustat (FG-
121. KDOQI Work Group. KDOQI Clinical Practice Guideline for 4592) for Treatment of Anemia in Pediatric Patients With
Nutrition in Children with CKD: 2008 update. Executive CKD [Internet] [cited 2022 Nov 30]. Available from: https:
summary. Am J Kidney Dis 2009;53:S11–104. https://doi.org/ //clinicaltrials.gov/ct2/show/NCT04925011 (30 November
10.1053/j.ajkd.2008.11.017. 2022, last date accessed).
122. Obeid W, Hiremath S, Topf JM. Protein restriction for CKD: 138. Seifert ME, Hruska KA. The kidney-vascular-bone axis
time to move on. Kidney360 2022;3:1611–5. https://doi.org/ in the chronic kidney disease-mineral bone disorder.
10.34067/KID.0001002022. Transplantation 2016;100:497–505. https://doi.org/10.1097/
123. Nelms CL. Optimizing enteral nutrition for growth in pedi- TP.0000000000000903.
atric chronic kidney disease (CKD). Front Pediatr 2018;6:214. 139. Ayoob RM, Mahan JD. Pediatric CKD-MBD: existing
https://doi.org/10.3389/fped.2018.00214. and emerging treatment approaches. Pediatr Nephrol
12 Chronic kidney disease in children

2022;37:2599–614. https://doi.org/10.1007/s00467-021- 152. Cirillo L, Ravaglia F, Errichiello C et al. Expectations in


05265-8. children with glomerular diseases from SGLT2 inhibitors.
140. Bonthuis M, Harambat J, Jager KJ et al. Growth in children on Pediatr Nephrol 2022;37:2997–3008. https://doi.org/10.1007/
kidney replacement therapy: a review of data from patient s00467-022-05504-6.
registries. Pediatr Nephrol 2021;36:2563–74. https://doi.org/ 153. Baigent C, Emberson J, Haynes R et al. Impact of dia-
10.1007/s00467-021-05099-4. betes on the effects of sodium glucose co-transporter-2
141. Goodman WG. Calcimimetic agents and secondary hy- inhibitors on kidney outcomes: collaborative meta-
perparathyroidism: treatment and prevention. Nephrol Dial analysis of large placebo-controlled trials. Lancet North
Transplant 2002;17:204–7. http://dx.doi.org/10.1093/ndt/17. Am Ed 2022;400:1788–801. https://doi.org/10.1016/S0140-
2.204. 6736(22)02074-8.

Downloaded from https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfad097/7140531 by guest on 10 September 2023


142. Warady BA, Ng E, Bloss L et al. Cinacalcet studies in pe- 154. Sen T, Heerspink HJL. A kidney perspective on the mech-
diatric subjects with secondary hyperparathyroidism re- anism of action of sodium glucose co-transporter 2 in-
ceiving dialysis. Pediatr Nephrol 2020;35:1679–97. https:// hibitors. Cell Metab 2021;33:732–9. https://doi.org/10.1016/
doi.org/10.1007/s00467-020-04516-4. j.cmet.2021.02.016.
143. A Study of Etelcalcetide in Pediatric Subjects With Sec- 155. Packer M. Critical reanalysis of the mechanisms underlying
ondary Hyperparathyroidism and Chronic Kidney Disease the cardiorenal benefits of SGLT2 inhibitors and reaffirma-
on Hemodialysis [Internet] [cited 2022 Dec 4]. Available tion of the nutrient deprivation signaling/autophagy hy-
from: https://clinicaltrials.gov/ct2/show/NCT03633708 (4 pothesis. Circulation 2022;146:1383–405. https://doi.org/10.
December 2022, last date accessed). 1161/CIRCULATIONAHA.122.061732.
144. Pearce D, Soundararajan R, Trimpert C et al. Collecting duct 156. McEwan P, Darlington O, Miller R et al. Cost-effectiveness
principal cell transport processes and their regulation. Clin of dapagliflozin as a treatment for chronic kidney dis-
J Am Soc Nephrol 2015;10:135–46. https://doi.org/10.2215/ ease: a health-economic analysis of DAPA-CKD. Clin J Am
CJN.05760513. Soc Nephrol 2022;17:1730–41. https://doi.org/10.2215/CJN.
145. Agarwal R, Kolkhof P, Bakris G et al. Steroidal and non- 03790322.
steroidal mineralocorticoid receptor antagonists in car- 157. Reifsnider OS, Kansal AR, Wanner C et al. Cost-
diorenal medicine. Eur Heart J 2021;42:152–61. https://doi. effectiveness of empagliflozin in patients with diabetic
org/10.1093/eurheartj/ehaa736. kidney disease in the United States: findings based on the
146. Epstein M. Hyperkalemia constitutes a constraint for im- EMPA-REG OUTCOME trial. Am J Kidney Dis 2022;79:796–806.
plementing renin-angiotensin-aldosterone inhibition: the https://doi.org/10.1053/j.ajkd.2021.09.014.
widening gap between mandated treatment guidelines 158. Tisdale RL, Cusick MM, Aluri KZ et al. Cost-effectiveness
and the real-world clinical arena. Kidney Int Suppl 2016;6:20– of dapagliflozin for non-diabetic chronic kidney disease.
8. J Gen Intern Med 2022;37:3380–7. https://doi.org/10.1007/
147. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone s11606-021-07311-5.
on chronic kidney disease outcomes in type 2 diabetes. 159. Vareesangthip K, Deerochanawong C, Thongsuk D et al.
N Engl J Med 2020;383:2219–29. https://doi.org/10.1056/ Cost-utility analysis of dapagliflozin as an add-on to stan-
NEJMoa2025845. dard of care for patients with chronic kidney disease
148. Pitt B, Agarwal R, Anker SD et al. Association of finerenone in Thailand. Adv Ther 2022;39:1279–92. https://doi.org/10.
use with reduction in treatment-emergent pneumonia and 1007/s12325-021-02037-6.
COVID-19 adverse events among patients with type 2 di- 160. Liu J, Cui J, Fang X et al. Efficacy and safety of dapagliflozin
abetes and chronic kidney disease: a FIDELITY pooled in children with inherited proteinuric kidney disease: a pi-
secondary analysis. JAMA Netw Open 2022;5:e2236123. lot study. Kidney Int Rep 2021;7:638–41. https://doi.org/10.
https://doi.org/10.1001/jamanetworkopen.2022.36123. 1016/j.ekir.2021.12.019.
149. Epstein M. Considerations for the future: current and fu- 161. Boeckhaus J, Gross O. Sodium-glucose cotransporter-2 in-
ture treatment paradigms with mineralocorticoid recep- hibitors in patients with hereditary podocytopathies, Al-
tor antagonists-unmet needs and underserved patient co- port Syndrome, and FSGS: a case series to better plan
horts. Kidney Int Suppl 2022;12:69–75. https://doi.org/10. a large-scale study. Cells 2021;10:1815. https://doi.org/10.
1016/j.kisu.2021.11.008. 3390/cells10071815.
150. A Study to Learn More About How Well the Study Treat- 162. Patry C, Fichtner A, Höcker B et al. Missing trial results: anal-
ment Finerenone Works, How Safe it is, How it Moves Into, ysis of the current publication rate of studies in pediatric
Through, and Out of the Body, and the Effects it Has on the dialysis from 2003 to 2020. Pediatr Nephrol 2023;38:227–36.
Body When Taken With an ACE Inhibitor or Angiotensin https://doi.org/10.1007/s00467-022-05553-x.
Receptor Blocker in Children With Chronic Kidney Disease 163. Landini S, Mazzinghi B, Becherucci F et al. Reverse pheno-
and Proteinuria - Full Text View - ClinicalTrials.gov [Inter- typing after whole-exome sequencing in steroid-resistant
net] [cited 2022 Dec 5]. Available from: https://clinicaltrials. nephrotic syndrome. Clin J Am Soc Nephrol 2020;15:89–100.
gov/ct2/show/NCT05196035 (5 December 2022, last date https://doi.org/10.2215/CJN.06060519.
accessed). 164. Bekheirnia N, Glinton KE, Rossetti L et al. Clinical utility
151. A Study to Learn More About How Safe the Study Treat- of genetic testing in the precision diagnosis and manage-
ment Finerenone is in Long-term Use When Taken With ment of pediatric patients with kidney and urinary tract
an ACE Inhibitor or Angiotensin Receptor Blocker Over 18 diseases. Kidney360 2021;2:90–104. https://doi.org/10.34067/
Months of Use in Children and Young Adults From 1 to 18 KID.0002272020.
Years of Age With Chronic Kidney Disease and Proteinuria 165. Domingo-Gallego A, Pybus M, Bullich G et al. Clinical
- Full Text View - ClinicalTrials.gov [Internet] [cited 2022 utility of genetic testing in early-onset kidney disease:
Dec 5]. Available from: https://clinicaltrials.gov/ct2/show/ seven genes are the main players. Nephrol Dial Transplant
NCT05457283 (5 December 2022, last date accessed). 2022;37:687–96. https://doi.org/10.1093/ndt/gfab019.

You might also like