Chronic Kidney Disease in Children Workup: Approach Considerations, CBC Count and Serum Chemistry Studies, Urine Studies (original) (raw)

Approach Considerations

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.

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CBC Count and Serum Chemistry Studies

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. [20]

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.

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Urine Studies

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.

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Novel Biomarkers

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. [21]

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Estimation of Glomerular Filtration Rate

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. [7, 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:

The value of k is different at different ages:

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. [22]

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.

Initial calculations used to estimate GFR in children relied heavily on serum creatinine concentration. A newer equation reflects well-recognized influences on creatinine levels (ie, muscle mass) and the introduction of cystatin C as a reliable marker of renal function. The “CKiD under 25” (also known as “U25”) is the most recently validated GFR estimating equation, which utilizes both age- and sex-specific constants “K” and incorporates creatinine as well as cystatin C. [23]

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Ultrasonography

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.

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Radionuclide Studies

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. [24]

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Kidney Biopsy and Histologic Features

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.

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Author

Sanjeev Gulati, MD, MBBS, DNB(Peds), DM, DNB(Neph), FIPN(Australia), FICN, FRCPC(Canada) Additional Professor, Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences; Senior Consultant in Pediatric Nephrology and Additional Director, Department of Nephrology and Transplant Medicine, Fortis Institute of Renal Sciences Transplantation, India

Sanjeev Gulati, MD, MBBS, DNB(Peds), DM, DNB(Neph), FIPN(Australia), FICN, FRCPC(Canada) is a member of the following medical societies: American Society of Pediatric Nephrology, International Society of Nephrology, Royal College of Physicians and Surgeons of Canada, Indian Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, The Scientific Research Honor Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD Tenured Professor of Pediatrics, The First Isaac A Abt, MD, Professor of Kidney Diseases (Emeritus), Northwestern University, The Feinberg School of Medicine; Staff Nephrologist, The Ann and Robert H Lurie Children’s Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Clinical Research, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Clinical Scientists, Cochrane Collaboration, International Bone and Mineral Society, International Conferences on Calcium Regulating Hormones, International Pediatric Nephrology Association, International Society of Nephrology, International Society of Renal Nutrition and Metabolism, Midwest Society for Pediatric Research, Pediatric Academic Societies, ROCK (Research on Calculus Kinetics) Society, Society for Pediatric Research

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Horizon Pharmaceuticals); Dicerna Pharmaceuticals
Incyte Pharmaceuticals; Eli Lilly for: Federation bio; Dicerna pharmaceuticals.

Additional Contributors

Laurence Finberg, MD Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine and Stanford University School of Medicine

Laurence Finberg, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.