Chronic Kidney Disease

Definition and Staging

Chronic kidney disease (CKD) is defined as kidney damage lasting for at least 3 months, characterized by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR).
Alternatively, it is defined as a GFR < 60 mL/min/1.73 m² for $\geq$ 3 months, with or without other signs of kidney damage.
Kidney damage manifests as abnormalities in blood or urine composition (e.g., persistent hematuria or proteinuria), abnormal imaging tests, or abnormalities on kidney biopsy.
Because renal maturation increases from infancy to reach adult values at approximately 2 years of age, standardized CKD stages based on GFR apply primarily to children older than 2 years.
The estimated GFR (eGFR) in children is most widely calculated using the bedside Schwartz equation.

Stages of Chronic Kidney Disease

Stage	GFR (mL/min/1.73 m²)	Clinical Description
1	$\geq$ 90	Kidney damage with normal or increased GFR.
2	60 - 89	Kidney damage with a mild decrease in GFR.
3a	45 - 59	Mildly to moderately decreased GFR.
3b	30 - 44	Moderately to severely decreased GFR.
4	15 - 29	Severe reduction in GFR.
5	< 15	Kidney failure (End-Stage Kidney Disease, ESKD); often requiring dialysis or transplantation.

Severity is additionally categorized by the degree of albuminuria using the urine protein-to-creatinine ratio (Up/Uc): A1 (Normal/mild <150 mg/g), A2 (Moderately increased 150-500 mg/g), and A3 (Severely increased >500 mg/g).

Etiology of CKD in Children

The etiology of pediatric CKD differs significantly from adult CKD (where diabetes and hypertension predominate) and varies by age at presentation.

Etiological Category	Specific Disorders and Prevalence
CAKUT (Congenital Anomalies of the Kidney and Urinary Tract)	The leading cause of pediatric CKD (28.1%); includes congenital obstructive uropathies (posterior urethral valves), renal hypoplasia/dysplasia, and reflux nephropathy.
Cystic, Hereditary, and Congenital Diseases	Accounts for ~15%; includes autosomal dominant/recessive polycystic kidney disease, nephronophthisis, Alport syndrome, cystinosis, and congenital nephrotic syndrome.
Secondary and Primary Glomerular Diseases	Accounts for ~11.4%; includes focal segmental glomerulosclerosis (FSGS), systemic lupus erythematosus (SLE) nephritis, hemolytic uremic syndrome (HUS), IgA nephropathy, and systemic vasculitis.
Tubulointerstitial Diseases	Accounts for ~4.9%; includes chronic interstitial nephritis, acute interstitial nephritis, and tubular necrosis.

Pathophysiology and Risk Factors for Progression

CKD is a continuum of disease, with increasing biochemical and clinical manifestations as renal function deteriorates.
Regardless of the primary etiology, once a critical loss of nephron mass occurs, compensatory mechanisms cause the remaining nephrons to undergo adaptive hyperfiltration and hypertrophy.
This hyperfiltration, combined with intraglomerular hypertension, leads to progressive tubulointerstitial fibrosis, which is the primary determinant of CKD progression.
Nonmodifiable risk factors for rapid disease progression include older age at onset, onset of puberty, glomerular etiology, and genetic predispositions.
Modifiable risk factors strongly associated with CKD progression include sustained hypertension, persistent nephrotic-range proteinuria, dyslipidemia, hyperuricemia, and a lack of renin-angiotensin-aldosterone system (RAAS) blockade.
Metabolic acidosis (time-varying serum bicarbonate <18 mmol/L) is another potent risk factor that contributes to complement pathway activation, inflammation, and progressive nephron loss.
Repeated episodes of acute kidney injury (AKI), such as those from dehydration, nephrotoxic medications (e.g., NSAIDs), or severe urinary tract infections, further accelerate the loss of functional renal parenchyma.

Clinical Manifestations and Complications

Children with CKD stages 1 to 3 (GFR >30 mL/min/1.73 m²) are frequently asymptomatic.
Patients with CAKUT or genetic tubulopathies typically present with growth failure, polyuria, polydipsia, and recurrent episodes of dehydration due to an impaired urinary concentrating ability.
Patients with glomerular diseases commonly present with edema, volume-dependent hypertension, gross or microscopic hematuria, and proteinuria.
As GFR progressively declines, uremic symptoms manifest, including severe fatigue, muscle weakness, nausea, vomiting, anorexia, and sleep disturbances.
Advanced CKD (Stage 4-5) is characterized by multiorgan complications such as hypertensive retinopathy, peripheral neuropathy, intense pruritus, purpura, and pericarditis.
Children with CKD face a 65% increased risk of neurocognitive impairment, particularly affecting attention, memory, inhibitory control, and academic achievement.

Specific Systemic Complications

Complication	Pathophysiology and Clinical Correlates
Growth Retardation	Driven by a growth hormone–resistant state (elevated GH but decreased insulin-like growth factor-1), malnutrition, metabolic acidosis, and renal osteodystrophy.
Anemia of CKD	Primarily results from inadequate erythropoietin (EPO) production by the peritubular interstitial cells. Exacerbated by iron/folate/vitamin B12 deficiency, and shortened erythrocyte survival due to uremia.
CKD-Mineral Bone Disease (CKD-MBD)	Driven by decreased renal 1-alpha-hydroxylation of 25-hydroxyvitamin D (calcitriol deficiency), leading to reduced intestinal calcium absorption and hypocalcemia. Concurrently, reduced GFR causes phosphate retention. These factors trigger severe secondary hyperparathyroidism, resulting in bone pain, skeletal deformities (rickets), and vascular calcification.
Cardiovascular Disease	Volume overload and RAAS activation lead to severe, refractory hypertension, left ventricular hypertrophy, and ischemic cardiomyopathy.

Diagnostic Evaluation

Initial evaluation must identify the underlying etiology and detect any reversible factors (e.g., urinary tract obstruction, active UTI, severe hypertension, dehydration, or concurrent drug toxicity).
Blood investigations should include complete blood counts, urea, creatinine, electrolytes, total protein, albumin, pH, and bicarbonate.
Assessment of CKD-MBD requires measuring serum calcium, phosphate, alkaline phosphatase, intact parathyroid hormone (PTH), and 25-hydroxyvitamin D.
Anemia workup mandates iron studies, including serum ferritin, transferrin, total iron-binding capacity, and percent transferrin saturation (TSAT).
Renal ultrasonography is routinely performed to evaluate kidney size, echogenicity, loss of corticomedullary differentiation, and to screen for structural CAKUT anomalies.
A kidney biopsy is indicated if there is an unexplained decline in kidney function, substantial new-onset proteinuria, or clinical suspicion of a progressive glomerular disease (e.g., IgA nephropathy or lupus nephritis).

Comprehensive Management

Optimal management requires a multidisciplinary team approach involving a pediatric nephrologist, specialized nurses, dietitians, and social workers.

Retarding Disease Progression

Strict blood pressure control is paramount; the target is to maintain systolic and diastolic pressures between the 50th and 75th percentiles for age, sex, and height.
Angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril) or angiotensin receptor blockers (ARBs) are the preferred first-line antihypertensive agents.
RAAS blockade provides significant renoprotection by reducing intraglomerular perfusion pressure, lowering proteinuria, and mitigating tubulointerstitial inflammation.
Potential nephrotoxins, including nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast agents, and specific herbal medications, must be strictly avoided.

Nutritional Support and Growth

Children must receive 100% of their estimated daily energy requirement for age, appropriately balanced between carbohydrates, unsaturated fats, and proteins.
Unlike in adults, dietary protein restriction is strictly NOT recommended in children due to the high risk of exacerbating growth failure and malnutrition; protein intake should meet 100% of the Dietary Reference Intake (DRI).
Supplemental enteral feeding via nasogastric or gastrostomy tubes is frequently necessary in infants and toddlers who cannot meet caloric goals orally.
Water-soluble vitamin supplementation (thiamine, riboflavin, folic acid, pyridoxine, and B12) is routinely required, especially for patients on dialysis.
Recombinant human growth hormone therapy (0.024–0.070 mg/kg/day, administered subcutaneously 6-7 times a week) is highly effective for treating severe short stature in patients with optimized nutrition and corrected metabolic derangements.

Management of Specific Complications

Therapy Target	Pharmacological and Clinical Interventions
Hypertension and Fluid Overload	In addition to ACEi/ARBs, therapy may require calcium channel blockers, beta-blockers, or loop diuretics (furosemide) for overt fluid overload. Severe refractory cases may necessitate centrally acting agents like clonidine.
Anemia	Iron supplementation (oral or intravenous) is initiated if TSAT is $\leq$ 20% or ferritin is $\leq$ 100 ng/mL. Iron-replete patients require recombinant human erythropoietin (50–150 U/kg/dose given 2-3 times a week) or Darbepoetin alfa, targeting a hemoglobin of 11–12 g/dL.
CKD-MBD (Bone Disease)	Dietary phosphate restriction (limiting dairy products) is the first step. Enteral phosphate binders (calcium carbonate or calcium acetate) are administered with meals. Active vitamin D metabolites, specifically 1,25-dihydroxyvitamin D3 (calcitriol), are required to suppress secondary hyperparathyroidism and optimize calcium absorption.
Metabolic Acidosis	Systemic alkalinization is achieved with oral sodium bicarbonate or sodium citrate solutions, which mitigates bone buffering and slows the progression of CKD.
Electrolyte Imbalance	Polyuric CAKUT patients require massive free water and salt supplementation. Conversely, oliguric patients with glomerular disease require strict sodium and potassium restriction to prevent fatal hyperkalemia and pulmonary edema.

Kidney Replacement Therapy (KRT)

Initiation of dialysis or preemptive transplantation is strongly recommended when the GFR falls below 8 to 12 mL/min/1.73 m², or earlier if intractable symptoms arise.
Indications for KRT include medically refractory fluid overload, severe therapy-resistant hypertension, persistent uremic gastrointestinal symptoms, profound growth retardation, and progressive neurological deterioration.
Chronic peritoneal dialysis (PD) is often the preferred initial modality in children as it can be performed at home via an automated cycler, providing steady clearance, fewer dietary restrictions, and allowing for uninterrupted schooling.
Kidney transplantation from a living-related or deceased donor is the ultimate, definitive therapy for pediatric ESKD, providing superior patient survival, improved neurocognitive outcomes, and the best potential for catch-up growth.