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NEPHROTIC SYNDROME IN CHILDREN: CURRENT MANAGEMENT AND
FUTURE PERSPECTIVES
Khamraliyeva
Yulduzkhon
Khakimovna
Assistant
of
the
Department
of
Pediatrics
and
Pediatric
Surgery,
CAMU
Eminov Ravshanjon Ikromjon ugli
Department of Faculty and Hospital Surgery, FMIOPH, Fergana, Uzbekistan
Abstract.
Pediatric nephrotic syndrome (NS) is a significant glomerular disorder marked by
heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia, predominantly affecting
children aged 1-6 years. This paper reviews the current understanding of NS, emphasizing
its pathophysiology, clinical presentation, diagnosis, and management strategies. Minimal
Change Disease (MCD) is the leading cause, accounting for 70-90% of cases, with
corticosteroids as the primary treatment, achieving remission in most cases. However,
relapses and steroid resistance necessitate alternative therapies like calcineurin inhibitors and
rituximab. Complications such as infections, thromboembolism, and growth retardation
highlight the need for comprehensive care. Future perspectives include genetic testing,
personalized medicine, and novel therapeutics to enhance outcomes and reduce steroid
dependency. This review underscores the importance of ongoing research and global
collaboration to refine treatment protocols and improve the quality of life for affected
children.
Keywords
: nephrotic syndrome, pediatric, minimal change disease, corticosteroids,
personalized medicine
Introduction
Nephrotic Syndrome (NS) is a prevalent glomerular disease in children, characterized by
heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia. It primarily affects
children aged 1-6 years, with an annual incidence of 2-7 per 100,000 children, and is more
common in males and certain ethnic groups, such as South Asians and Africans[1,2]. The
syndrome is classified into primary, secondary, and congenital types. Primary NS, often
idiopathic, is most commonly caused by Minimal Change Disease (MCD), which accounts
for 70-90% of cases in children and is highly responsive to corticosteroids[3,4]. Secondary
causes include systemic diseases like systemic lupus erythematosus, infections, and drug
exposure[4,5]. The pathogenesis involves increased glomerular permeability due to various
mechanisms, including immune factors and genetic mutations[6]. Management of NS
primarily involves corticosteroids, with prednisone being the first-line treatment for MCD,
leading to remission in up to 95% of cases[3]. However, relapses are common, and
alternative therapies such as calcineurin inhibitors and rituximab are used for steroid-
resistant cases[7,8]. Complications of NS include infections, thromboembolism, and acute
kidney injury, necessitating careful monitoring and adjunctive therapies like albumin and
diuretics for edema[4,8]. Future directions in NS management focus on reducing steroid-
related side effects and exploring genetic and biomarker research to better understand and
treat the disease[6,7]. Overall, while the prognosis for steroid-responsive NS is generally
good, ongoing research and international collaboration are essential to improve outcomes
and develop evidence-based recommendations[2,9].
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Pathophysiology and classification
Pediatric nephrotic syndrome is primarily characterized by massive proteinuria,
hypoalbuminemia, and edema, with its pathophysiology deeply rooted in podocyte injury
and immune dysregulation. Podocytes, specialized cells in the kidney, play a crucial role in
maintaining the glomerular filtration barrier, and their dysfunction is central to the
development of nephrotic syndrome. In conditions like Minimal Change Disease (MCD)
and Focal Segmental Glomerulosclerosis (FSGS), podocyte injury leads to the effacement of
foot processes, disrupting the filtration barrier and resulting in proteinuria[10–12]. MCD, the
most common form in children, is often associated with immune dysregulation, where T-cell
mediated events and circulating factors like angiopoietin-like-4 (ANGPTL4) contribute to
podocyte damage. This condition is typically steroid-responsive, although the exact
mechanisms remain partially understood[13,14]. In contrast, FSGS is characterized by
segmental scarring of the glomeruli and is often resistant to steroid treatment. It involves
structural changes in podocytes and is associated with circulating factors such as soluble
urokinase receptor (suPAR), which are not present in MCD[14,15]. Membranous
Nephropathy, although rare in children, involves immune complex deposition on the
glomerular basement membrane, leading to podocyte injury[13]. Genetic factors also play a
significant role, with mutations in podocyte-specific genes like NPHS1 and NPHS2
contributing to disease susceptibility and variability in treatment response[10,16]. The
classification of nephrotic syndrome into MCD, FSGS, and Membranous Nephropathy is
based on histological findings, with MCD showing minimal changes under light microscopy,
FSGS displaying segmental sclerosis, and Membranous Nephropathy characterized by
thickened glomerular capillary walls[17]. Understanding these pathophysiological
mechanisms is crucial for developing targeted therapies that address the underlying causes
rather than just managing symptoms, potentially improving patient outcomes and reducing
reliance on corticosteroids[10,11].
Clinical presentation
Pediatric nephrotic syndrome is classically characterized by a tetrad of clinical symptoms:
edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Edema is often the most
noticeable symptom, presenting as swelling in areas such as the eyelids, abdomen, and
extremities, and is due to fluid retention caused by low serum albumin levels[3,18].
Proteinuria, defined as a urine protein excretion rate greater than 40 mg/m² per hour, is a
hallmark of the syndrome and can be measured using a 24-hour urine collection or estimated
via a spot urine protein-to-creatinine ratio[3,19]. Hypoalbuminemia, with serum albumin
levels typically below 2.5 g/dL, results from the loss of protein in the urine[20].
Hyperlipidemia, often manifesting as elevated cholesterol levels, is another common feature,
although not indispensable for diagnosis[21]. Minimal change disease (MCD) is the most
prevalent cause of nephrotic syndrome in children, accounting for 70% to 90% of cases, and
is generally responsive to corticosteroid treatment[3,14]. However, clinicians should be
vigilant for atypical presentations or red flags that may suggest alternative diagnoses or
complications. These include the presence of hypertension, hematuria, or onset of symptoms
in children younger than one year or older than puberty, which decrease the likelihood of
MCD and may indicate other conditions such as focal segmental glomerulosclerosis or
secondary causes like infections and systemic diseases[3,7]. Additionally, congenital
nephrotic syndrome, presenting within the first three months of life, is rare but associated
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with high morbidity and mortality, often requiring early intervention[22,23]. Clinicians
should also be aware of potential complications such as infections, thromboembolism, and
acute kidney injury, which necessitate careful monitoring and management[7,24]. Early and
accurate diagnosis, along with appropriate treatment, is crucial to improving outcomes and
preventing long-term sequelae in children with nephrotic syndrome[3,19].
Diagnosis
Pediatric nephrotic syndrome is diagnosed using a combination of clinical evaluation and
laboratory tests, with urinalysis and blood tests being primary tools. Urinalysis with a spot
protein/creatinine ratio is crucial, as a ratio greater than 2.5 is diagnostic of nephrotic
syndrome, especially when intermittent proteinuria is excluded[3]. Blood tests measuring
albumin, cholesterol, urea, and creatinine levels help assess the severity and impact of the
syndrome, as hypoalbuminemia and hyperlipidemia are characteristic features[3,7]. Renal
ultrasound is often employed to evaluate kidney size and structure, although it is not
diagnostic for nephrotic syndrome itself[25]. Renal biopsy is a more invasive diagnostic tool
and is typically reserved for specific circumstances. It is indicated in cases of steroid-
resistant nephrotic syndrome, frequent relapses, or when a diagnosis other than minimal
change disease (MCD) is suspected[6,26]. In children over the age of 10, a renal biopsy is
often recommended at diagnosis due to a higher likelihood of non-MCD causes, although
recent studies suggest it may be unnecessary in steroid-sensitive cases[27]. Biopsy is also
considered when atypical symptoms such as hypertension, hematuria, or renal failure are
present, as these may indicate more severe glomerular lesions[28]. The procedure is
generally safe, with complications such as hematuria and hematoma being relatively rare[26].
Ultimately, the decision to perform a renal biopsy should weigh the potential diagnostic
benefits against the risks, particularly in younger children who may require sedation or
anesthesia[25].
Current management strategies
Pediatric nephrotic syndrome (NS) is a prevalent glomerular disease characterized by
proteinuria and hypoalbuminemia, with corticosteroids being the cornerstone of initial
treatment. The standard regimen involves prednisone or prednisolone at 60 mg/m²/day for
six weeks, followed by 40 mg/m²/day on alternate days for another six weeks, which induces
remission in most cases, classifying them as steroid-sensitive nephrotic syndrome
(SSNS)[29,30]. However, 20% of children do not respond to steroids, leading to a
classification of steroid-resistant nephrotic syndrome (SRNS), which often requires second-
line therapies such as calcineurin inhibitors (cyclosporine or tacrolimus)[29,31]. For those
who relapse frequently or become steroid-dependent, steroid-sparing agents like
mycophenolate mofetil (MMF), cyclophosphamide, and rituximab are considered, with
MMF being preferred due to its favorable side effect profile[29,32,33]. Supportive care is
crucial and includes diuretics for edema, salt restriction, and the use of ACE inhibitors or
ARBs to manage hypertension and reduce proteinuria[30]. Additionally, managing
complications such as infections and thrombotic events is vital, with prophylactic antibiotics
and anticoagulants being recommended in high-risk patients[8,30]. The choice of treatment
is often individualized based on the severity of the disease, patient age, and drug tolerability,
aiming to achieve remission while minimizing side effects[31,34]. Despite the effectiveness
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of these strategies, the pathophysiology of NS remains elusive, and ongoing research is
needed to optimize treatment protocols and improve patient outcomes[31,35].
Complications
Pediatric nephrotic syndrome (NS) is associated with a range of complications, both disease-
related and treatment-induced. Infections are a significant concern, with peritonitis and
cellulitis being common due to the immunocompromised state induced by proteinuria and
hypoalbuminemia. Cellulitis, often caused by bacteria such as Streptococcus and
Staphylococcus, is marked by redness, swelling, and pain, and requires prompt antibiotic
treatment[36]. Thromboembolic events, including venous thromboembolism and pulmonary
embolism, are also prevalent due to hypercoagulability associated with NS[37]. Growth
retardation is another complication, often exacerbated by long-term corticosteroid use,
which can lead to short stature and other growth issues[38]. Corticosteroids, the mainstay of
NS treatment, are linked to several adverse effects, including hypertension, obesity,
osteoporosis, and behavioral disturbances[38,39]. These side effects necessitate the use of
steroid-sparing agents to maintain remission and minimize long-term impacts[38].
Additionally, NS can lead to cardiovascular complications such as hyperlipidemia, which
further complicates the disease management[40]. The risk of acute kidney injury and other
renal complications is heightened during disease relapses, emphasizing the need for regular
monitoring and early intervention[41]. Overall, the management of pediatric NS requires a
comprehensive approach to address both the disease and its complications, with a focus on
minimizing the side effects of long-term corticosteroid therapy to improve patient
outcomes[8,37].
Future perspectives
The future management of pediatric nephrotic syndrome (NS) is poised for significant
advancements through the integration of genetic testing, personalized medicine, artificial
intelligence, novel therapeutics, and improved vaccination strategies. Genetic testing plays a
crucial role, especially for congenital and steroid-resistant cases, as it helps identify
monogenic causes in approximately 30% of childhood-onset steroid-resistant nephrotic
syndrome (SRNS) cases, thereby guiding treatment decisions and avoiding unnecessary
procedures like kidney biopsies[42,43]. The use of next-generation sequencing (NGS) and
whole-exome sequencing (WES) has enhanced the diagnostic accuracy for these conditions,
allowing for early and precise interventions[44,45]. Personalized medicine is further
advanced by the identification of specific biomarkers and molecular diagnostics, which
enable tailored therapeutic strategies based on individual genetic profiles. This approach is
complemented by the development of patient-specific kidney organoid models and
pharmacogenomics, which promise to refine treatment options and improve outcomes.
Artificial intelligence (AI) is increasingly being integrated into prediction and treatment
planning, offering potential improvements in the accuracy of prognosis and the
customization of treatment regimens[46]. In terms of therapeutics, novel immunomodulators
and biologics, such as monoclonal antibodies and stem cell therapies, are being explored to
address the challenges of SRNS, which is often resistant to conventional treatments[47].
These advancements are crucial for reducing the progression to end-stage renal disease
(ESRD) and improving the quality of life for affected children[43]. Additionally, improved
vaccination strategies are essential for immunocompromised patients, ensuring they are
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protected against infections without exacerbating their underlying condition[6]. Collectively,
these innovations represent a comprehensive approach to managing pediatric nephrotic
syndrome, emphasizing early diagnosis, personalized treatment, and preventive care to
enhance patient outcomes[6,48,49].
Conclusion
Pediatric nephrotic syndrome remains a complex yet manageable condition, with significant
strides made in its diagnosis and treatment. Advances in understanding podocyte injury and
immune dysregulation have paved the way for targeted therapies, while genetic testing and
personalized medicine offer hope for more precise interventions. Despite challenges such as
relapses and treatment-related complications, the integration of novel therapeutics, artificial
intelligence, and improved vaccination strategies promises a brighter future for affected
children. By fostering international collaboration and prioritizing research into biomarkers
and steroid-sparing agents, the medical community can transform the management of
nephrotic syndrome, ensuring better outcomes and enhanced quality of life for young
patients worldwide.
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