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https:/doi.org/10.1093/ckj/sfad097
Advance Access Publication Date: 24 April 2023
CKJ Review
CKJ REVIEW
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.
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
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)
top
abnormalities, low nephron endowment, etc.
ocy
G1 ≥ 90
Pod
40%
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-
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
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
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].
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