Chronic Kidney Disease/End-Stage Kidney Disease (CKD/ESKD)

Definition and Staging

Definition: The Kidney Disease Improving Global Outcome (KDIGO) initiative defines chronic kidney disease (CKD) as one or more of the following criteria for ≥3 months:

• glomerular filtration rate (GFR) <90 mL/min per 1.73 m²

• risk factors for and markers indicative of kidney damage

  • albuminuria

  • abnormal urinary sediment (marked by hematuria, pyuria, or cellular casts)

  • tubular dysfunction

  • structural abnormalities (e.g., solitary kidney, renal dysplasia/hypoplasia, scarring)

  • prior kidney transplantation

Staging: The KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease classifies CKD in stages based on GFR and albuminuria as follows:

KDIGO: Prognosis of CKD by GFR and Albuminuria Categories

• The categories of GFR range from G1 (normal or high; GFR ≥90 mL/min per 1.73 m²) to G5 (kidney failure; GFR <15 mL/min per 1.73 m²).

• Category G3 is further split into G3a and G3b, with the long-term prognosis for G3b being worse than that of G3a.

• Within each GFR category, albuminuria can be categorized as A1 (normal to mildly increased; <30 mg/g), A2 (moderately increased; 30-300 mg/g), or A3 (severely increased; >300 mg/g), in order of worsening prognosis.

(Source: KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International 2024.)

Methods for estimating GFR (eGFR): The gold standard for measuring GFR involves expensive and complex methods (e.g., 24-hour urine creatinine clearance, nuclear medicine GFR study, and measurement of inulin clearance from the blood into the urine). Therefore, formulas have been developed in adults to estimate GFR (e.g., Modification of Diet in Renal Disease [MDRD] or CKD-Epidemiology [CKD-EPI]) using a spot serum creatinine level and anthropometric data to calculate creatinine clearance. The modified or bedside Schwartz equation, derived in 2009 from the CKiD cohort data, is used to estimate creatinine clearance in children ages 1-18 years:

The Bedside Schwartz Equation

Etiology

Chronic kidney disease in children is caused by a heterogeneous group of etiologies. The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) is a voluntary research group established in 1987 that monitors epidemiologic data and outcomes in children with end-stage kidney disease (ESKD), including those receiving renal replacement therapy or who have received renal transplantation in North America. NAPRTCS's last annual report, published in 2014, included cumulative data on etiologies of ESKD in more than 11,000 pediatric transplantation patients.

ESKD may be a more insidious process than previously thought. In a 2018 study, a history of kidney disease in childhood that had resolved by age 18 years (normal eGFR and renal function) was associated with increased risk of developing ESKD over a 30-year follow-up period.

Complications of CKD and Treatment

The kidney performs multiple vital functions to maintain homeostasis. CKD can cause many complications that must be medically optimized in children to maintain adequate growth and development.

Growth and Nutrition

Children with CKD suffer from poor growth. Etiologies include malnutrition, cachexia, feeding intolerance, and growth hormone resistance.

• Treatment: Besides encouraging increased nutritional intake, recombinant growth hormone (rGH) has been demonstrated to improve linear growth in children with CKD, without compromising BMI or eGFR. For more information on nutrition in CKD, see Nutritional Management of Chronic Kidney Disease.

Anemia

The kidney is the organ responsible for production of erythropoietin, a vital protein that stimulates erythropoiesis in the bone marrow. CKD leads to both a decline in the production of erythropoietin and chronic malnutrition, causing iron, folate, and vitamin B₁₂ deficiencies.

• Treatment includes restoration of micronutrients and iron stores, as well as the use of erythropoiesis-stimulating agents (ESAs) to improve hemoglobin (Hgb) and hematocrit (Hct) levels and avoid the need for multiple red blood cell transfusions.

  • Targeting a normal or high hemoglobin level in patients with CKD may not lead to improved outcomes. A randomized trial conducted in adults with CKD demonstrated higher rates of death and hospitalization in patients treated at a higher hemoglobin target (13.5 g/dL), compared with adults with CKD treated at a lower target (11.3 g/dL).

  • In the PIVOTAL trial, patients on maintenance hemodialysis who received high-dose iron regimens seemed to experience better primary outcomes and less ESA use than those on low-dose iron regimens.

  • KDIGO guidelines recommend that all pediatric CKD patients requiring ESA therapy have a target Hgb of 11-12 g/dL.

CKD-Mineral and Bone Disorder (MBD)

As CKD progresses, the kidney loses its ability to maintain the calcium-vitamin D-parathyroid (PTH) feedback loop essential in calcium and phosphorus homeostasis. Therefore, CKD leads to unchecked stimulation of PTH (secondary hyperparathyroidism) manifesting as bone resorption/rickets, hyperphosphatemia, and hypocalcemia. Fibroblast growth factor 23 (FGF-23) is a hormone that has also been recently shown to play an early role in the development of secondary hyperparathyroidism and the development of MBD.

• Treatment includes therapies to maintain calcium-vitamin D-PTH homeostasis and to limit hyperphosphatemia.

  • Therapies for CKD-MBD include dietary restrictions of phosphorus and supplementation with calcium and vitamin D. Activated vitamin D, vitamin D analogs, and calcimimetics also can reduce secondary hyperparathyroidism.

  • For further information, refer to the 2017 KDIGO guidelines on CKD-MBD.

Hypertension and Cardiovascular Disease

Activation of the renin-angiotensin system in CKD is responsible for hypertension. Up to 50% of patients with CKD have hypertension, and 75% of those with ESKD (stage V CKD or requiring dialysis) have uncontrolled hypertension. Adult patients with untreated hypertension are at increased risk for developing poor cardiovascular outcomes.

• Treatment: Aggressive control of blood pressure (BP) with one or more agents is paramount in preventing morbidity and mortality.

  • The ESCAPE trial, published in 2009, demonstrated that strict BP control (target 24-hour mean arterial pressure below the 50th percentile) in children with CKD reduced the decline in eGFR, delaying the progression of renal disease.

Uremia and Neurocognition

Patients with severe CKD are unable to process the byproducts of protein metabolism. As a result, rising blood urea nitrogen (BUN) levels can cause toxic adverse effects. Symptoms of uremia are broad, can be nonspecific, and are not associated with a specific BUN level. General symptoms include drowsiness, poor school performance, irritability, lack of energy, poor appetite, nausea, bruising (resulting from platelet dysfunction), pallor/grey skin, and cardiomyopathy. Recognizing symptoms of uremia is important because they are one indication for initiation of renal replacement therapy. Even patients with mild-to-moderate CKD and who are otherwise asymptomatic can demonstrate a decline in neurocognitive function.

• Treatment: Symptoms of uremia are one indication for the initiation of dialysis or kidney transplantation.

Dialysis and Transplantation

Dialysis: Initiation of dialysis in children with worsening kidney disease is dependent on several factors, including symptom severity and physician or medical center assessment of disease burden. Indications for dialysis include eGFR<10-20 mL/min/1.73 m² or symptoms of CKD that cannot be medically managed (typically uremia). Modalities for dialysis include:

• Peritoneal dialysis requires a catheter placed into the child’s abdomen, and dialysis is performed daily (typically at night).

• Hemodialysis requires large-bore vascular access and is performed three to four times per week. Vascular access can be achieved via a tunneled central venous catheter, arteriovenous fistula, or synthetic arteriovenous graft.

  • In contrast with renal replacement therapy in most adults on such therapy, dialysis in children is typically viewed as a mode of renal replacement therapy meant as a bridge to renal transplantation.

Renal transplantation is a mode of renal replacement therapy that is also not permanent. Most allografts last 8-15 years, depending on multiple factors (e.g., medication adherence, underlying etiology of ESKD, disease recurrence, type of transplantation).

• In the United States, pediatric patients receive preference on the deceased donor transplantation list. Approximately 60% of pediatric renal transplantations are performed via deceased donor and 40% are performed as living donor. Nearly 28% of transplantations are performed preemptively, prior to the initiation of dialysis.