Chronic Kidney Disease in Children Workup

Initial testing in a child with suspected chronic kidney disease (CKD) must include an examination of the urine and estimation of the glomerular filtration rate (GFR). An important aspect of this initial evaluation is the determination of disease duration. Although the distinction between acute, subacute, and chronic kidney disease or failure is arbitrary, the differential diagnosis can frequently be narrowed if the disease duration is known. This assessment is best performed by comparing the current urinalysis or plasma creatinine concentration (PCr) with previous results, if available.

Imaging studies such as ultrasonography and radionuclide studies help in confirming the diagnosis of chronic kidney disease and may also provide clues to its etiology.

Anemia is an important clinical finding in chronic kidney disease (CKD), and a complete blood cell (CBC) count is an important investigation both in the initial evaluation and the subsequent follow-up in these children. Anemia may indicate the chronic nature of the renal failure in the absence of any other obvious causes and may also be a clue to the underlying cardiovascular disease. ^[16]

Serum chemistry testing provides a valuable diagnostic tool both in the initial diagnosis and in the subsequent follow-up in these children. Blood urea nitrogen (BUN) and serum creatinine assessments are the most important tests. Estimation of the serum sodium, potassium, calcium, phosphorus, bicarbonate, alkaline phosphatase, parathyroid hormone (PTH), and cholesterol and fractionated lipid levels are important in the treatment and prevention of various chronic kidney disease–related complications.

Urine examination is perhaps the most important test and should be considered a part of the physical examination in all children being screened or evaluated for chronic kidney disease (CKD). It can be performed at the bedside or in the clinic using a fresh urine sample.

Urine dipstick and microscopy

An initial evaluation consists of a multitest detection strip (dipstick) test, followed by urine microscopy. The dipstick is a quick method of screening and detecting proteinuria, hematuria, and pyuria and provides an estimate of the specific gravity (urine-concentrating capacity).

Urine microscopy is performed on a centrifuge-spun urine specimen to look for red blood cells (RBCs), white blood cells (WBCs), and casts. Most children with chronic kidney disease have broad hyaline casts. Characteristic findings on microscopic examination of the urine sediment may suggest a diagnosis other than chronic kidney disease. As an example, the presence of muddy-brown granular casts and epithelial cell casts is highly suggestive of acute tubular necrosis, whereas RBC casts would suggest an acute nephritic process.

Proteinuria and albuminuria analysis

The most appropriate, practical, and precise method for estimation of proteinuria in children is to calculate the protein-to-creatinine ratio in a spot urine specimen. Patients with a positive dipstick test finding (1+ or greater) should undergo quantitative measurement (protein-to-creatinine ratio or albumin-to-creatinine ratio) within 3 months to confirm proteinuria. When postpubertal children with diabetes mellitus of 5 or more years' duration are screened, albumin should be measured in a spot urine sample using either albumin-specific dipstick or albumin-to-creatinine ratio testing.

Although elevated serum creatinine and proteinuria are the most frequently utilized biomarkers of chronic kidney disease (CKD), creatinine and proteinuria increase relatively late in the course of kidney damage and progression in CKD. Novel biomarkers may identify children with the earliest stages of injury and repair, before proteinuria or serum creatinine identifies irreversible injury and nephron loss.

Because CKD progression involves multiple processes in the kidney, it is unlikely that one biomarker will best predict glomerular filtration rate (GFR) decline. It is likely that panels of biomarkers that leverage the additive properties of each individual biomarker will be the most useful clinical tools in identifying risk of CKD progression in children. A panel of biomarkers that represent the multifactorial pathophysiologic mechanisms leading to CKD progression, including tubulointerstitial injury, fibrosis, inflammation, and repair, may prove useful for predicting GFR decline in children.

A study showed that urine neutrophil gelatinase-associated lipocalin (NGAL) predicted CKD progression, but this biomarker did not significantly improve on a clinical model of CKD risk factors, including estimated glomerular filtration rate (eGFR) and proteinuria. However, tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) had a strong association with progression to end-stage renal disease (ESRD) even after controlling for albuminuria and eGFR. ^[17]  

The glomerular filtration rate (GFR) is equal to the sum of the filtration rates in all of the functioning nephrons; thus, estimation of the GFR gives a rough measure of the number of functioning nephrons. A reduction in GFR implies progression of the underlying disease.

The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines state that estimates of GFR are the best overall indices of the level of kidney function. ^[4] The reference range of GFR in young adults is 120-130 mL/min per 1.73 m². However, the reference range of estimated GFR (eGFR) is much lower in early infancy, even when corrected for body surface area, and subsequently increases in relationship to body size for as long as 2 years. Hence, the eGFR ranges that are used to define the 5 CKD stages apply only to children aged 2 years and older (see Staging). The eGFR can be estimated from the constant k, plasma creatinine concentration (PCr) (in mg/dL), and body length (L) (in cm) according to the Schwartz formula, as follows:

• GFR = (k X L) / PCr

The value of k is different at different ages:

• k = 0.4 for preterm infants),

• k = 0.45 for full-term infants

• k = 0.55 for those aged 2-12 years in children and adolescent girls

• k = 0.7 years in adolescent boys

Therefore, all children with chronic kidney disease should have an eGFR calculated. This should be calculated from the Schwartz (or Counahan-Barratt prediction) equation in children, because it is convenient, reasonably precise, and practical. The constants used in the equations differ slightly, likely related to the different assays to measure creatinine.

Creatinine clearance estimates are difficult and imprecise, because they require 24-hour urine collections, which may be incomplete for various reasons. It is a known fact that estimation of GFR or creatinine clearance from serum creatinine critically depends on calibration of the serum creatinine assay, specific to the expected lower levels found in children without chronic kidney disease.

For young adults, the Chronic Kidney Disease in Children study (CKiD) formula underestimates eGFR, whereas the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula overestimates eGFR. Averaging results from the 2 formulas provided an eGFR similar to an iohexol GFR. Cystatin C–based equations do not outperform the creatinine-based formulas in the general population and are therefore not recommended for routine assessment of kidney function but may be considered for special clinical situations in which patients have reduced muscle mass. ^[18]

Plasma cystatin C concentration

Because of the problems with changes in creatinine production and secretion, other endogenous compounds have been evaluated in an effort to provide a more accurate estimation of GFR. Perhaps the most promising is cystatin C, a low–molecular-weight protein that is a member of the cystatin superfamily of cysteine protease inhibitors. Cystatin C is produced by all nucleated cells, and its rate of production is relatively constant and is unaltered by inflammatory conditions or changes in diet. The plasma cystatin C concentration may correlate more closely with the GFR than with the PCr.

Ultrasonography is a commonly used radiographic technique in patients who present with kidney disease because of its safety, its ease of use, and the information this modality provides. Because obstruction is a readily reversible disorder, all patients who present with acute or chronic failure of unknown etiology should undergo ultrasonography, the modality of choice to assess possible obstructive disease. Although less sensitive than computed tomography (CT) scanning in initially revealing a renal mass, ultrasonography can be useful in differentiating a simple benign cyst from a more complex cyst or a solid tumor. This technique is also commonly used to screen for and to diagnose types of polycystic kidney disease.

Early detection of renal scarring is possible with radioisotope scanning with 99m (^99m)-technetium dimercaptosuccinic acid (DMSA). This imaging modality is more sensitive than intravenous pyelography (IVP) in detecting renal scars and is considered the criterion standard for diagnosing reflux nephropathy, if present.

Voiding cystourethrography

Voiding cystourethrography can be performed with a radionuclide tracer study and is used to detect vesicoureteral reflux.

Retrograde or anterograde pyelography

Antegrade or retrograde pyelography may be used to better diagnose and relieve urinary tract obstruction; however, the use of pyelography for the diagnosis of obstruction has largely been supplanted by ultrasonography and computed tomography (CT) scanning. Nonetheless, antegrade or retrograde pyelography may be indicated when the clinical history is highly suggestive (unexplained acute renal failure with a bland urine sediment in a patient with known pelvic malignancy) despite ultrasonography and CT scanning findings being negative for hydronephrosis (because of possible ureteral encasement). Consultation with a pediatric urologist is suggested if antegrade or retrograde pyelography is considered.

Skeletal survey

A skeletal survey is useful in evaluating for secondary hyperparathyroidism, a component of osteodystrophy, as well as for bone-age estimation before starting or in continuation of growth hormone therapy. ^[19]

A renal biopsy is commonly performed in patients with suspected glomerulonephritis or vasculitis and in those with otherwise unexplained chronic kidney disease (CKD) or acute kidney failure. If a child has small shrunken kidneys, a kidney biopsy is often unnecessary to establish a diagnosis of chronic kidney disease.

In advanced stages of chronic kidney disease, irrespective of the underlying etiology, the findings often consist of segmental and globally sclerosed glomeruli and tubulointerstitial atrophy, often with tubulointerstitial mononuclear infiltrates.