Approach Considerations
Testing in patients with chronic kidney disease (CKD) typically includes a complete blood count (CBC), basic metabolic panel, and urinalysis, with calculation of renal function. Normochromic normocytic anemia is commonly seen in CKD. Other underlying causes of anemia should be ruled out.
The blood urea nitrogen (BUN) and serum creatinine levels will be elevated in patients with CKD. Hyperkalemia or low bicarbonate levels may be present. Serum albumin levels may also be measured, as patients may have hypoalbuminemia as a result of urinary protein loss or malnutrition. A lipid profile should be performed in all patients with CKD because of their risk of cardiovascular disease.
Serum phosphate, 25-hydroxyvitamin D, alkaline phosphatase, and intact parathyroid hormone (PTH) levels are obtained to look for evidence of renal bone disease. Renal ultrasonography and other imaging studies may be indicated.
Measurement of serum cystatin C levels is gaining a greater role in the estimation of kidney function. [44] Cystatin C is a small protein that is expressed in all nucleated cells, produced at a constant rate, and freely filtered by the glomerulus; it is not secreted but is instead reabsorbed by tubular epithelial cells and catabolized, so it does not return to the bloodstream. These properties make it a valuable endogenous marker of renal function. [45] A study that used cystatin C instead of creatinine to estimate glomerular filtration rate (GFR) concluded that cystatin C–based GFR equations outperform creatinine-based formulas in obese CKD patients, especially those with a body mass index (BMI) ≥35 kg/m2 and in obese women. [46]
In certain cases, the following tests may be ordered as part of the evaluation of patients with CKD:
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Serum and urine protein electrophoresis, serum and urine free light chains: Screen for a monoclonal protein possibly representing multiple myeloma
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Antinuclear antibodies (ANA), double-stranded DNA antibody levels: Screen for systemic lupus erythematosus
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Serum complement levels: Results may be depressed with some glomerulonephritides
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Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA) levels: Positive findings are helpful in the diagnosis of granulomatosis with polyangiitis (Wegener granulomatosis); a positive P-ANCA result is also helpful in the diagnosis of microscopic polyangiitis
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Anti–glomerular basement membrane (anti-GBM) antibodies: Their presence is highly suggestive of underlying Goodpasture syndrome
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Hepatitis B and C, human immunodeficiency virus (HIV), Venereal Disease Research Laboratory (VDRL) serology: These conditions are associated with some glomerulonephritides
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Imaging studies and consideration of bladder function studies: These evaluate for possible obstruction and other urologic abnormalities
Screening
Evidence-based recommendations from the American College of Physicians (ACP) regarding the screening, monitoring, and treatment of adults with stage 1-3 CKD recommend against CKD screening for asymptomatic adults with no risk factors for kidney disease. The ACP’s position, however, has been disputed by the American Society of Nephrology (ASN). [47, 48, 49]
The ACP recommendations, issued in October 2013, are as follows [47, 49] :
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Asymptomatic adults without risk factors for CKD should not be screened for the disease (Grade: weak recommendation, low-quality evidence)
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Adults with or without diabetes who are currently taking an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II-receptor blocker (ARB) should not be tested for proteinuria (Grade: weak recommendation, low-quality evidence)
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In treating patients with hypertension and stage 1-3 CKD, clinicians should select pharmacologic therapy that includes either an ACE inhibitor (moderate-quality evidence) or an ARB (high-quality evidence) (Grade: strong recommendation)
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Elevated low-density lipoprotein levels in patients with stage 1-3 CKD should be managed with statin therapy (Grade: strong recommendation, moderate-quality evidence)
The ASN, however, in response to the ACP recommendations, released a statement strongly advocating CKD screening even in patients without risk factors for CKD. The ASN pointed out that early CKD is usually asymptomatic and that catching and treating it early may slow its development. [48]
The nephrology society also disagreed with the ACP’s recommendation against testing for proteinuria, whether or not diabetes is present, in adults taking an ACE inhibitor or an ARB, emphasizing the importance of renal health assessment in adults on antihypertensive medication. [48]
The See Kidney Disease (SeeKD) targeted screening project identified a high proportion of individuals with risk factors for CKD and a high prevalence of unrecognized CKD. Participants with at least one risk factor for CKD (eg, diabetes, hypertension, vascular disease, family history of kidney problems) received a point-of-care creatinine measurement. Of the 5194 participants screened, 18.8% had unrecognized CKD (estimated GFR [eGFR] < 60 ml/min/1.73 m2); 13.8% had stage 3a CKD (eGFR 45-60 ml/min/1.73 m2). [50]
Urinalysis
In adult patients who are not at elevated risk for CKD, screening with total protein can be done with a standard urine dipstick, according to guidelines from the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI). If the dipstick test is positive (1+ or greater), patients should undergo testing for confirmation of proteinuria. [51]
Although 24-hour urine collection for total protein and creatinine clearance (CrCl) can be performed, spot urine collection for total protein–to-creatinine (P/C) ratio allows reliable approximation (extrapolation) of total 24-hour urinary protein excretion. In children, teenagers, and young adults in particular, a first morning urine specimen is preferable to a random specimen, as so-called orthostatic proteinuria (considered benign) can be excluded.
Patients with a P/C ratio above 200 mg/mg should undergo a full diagnostic evaluation. [51] A value of greater than 300-350 mg/mg is within the nephrotic range.
For screening patients at elevated risk, the KDOQI recommends using an albumin-specific dipstick; this is because albuminuria is a more sensitive marker than total protein for CKD from diabetes, hypertension, and glomerular diseases. A positive dipstick test should be followed by calculation of the albumin-to-creatinine ratio, with a ratio greater than 30 mg/mg followed by a full diagnostic evaluation. [51]
For monitoring proteinuria in adults with CKD, the KDOQI recommends measuring the P/C ratio in spot urine samples, using the albumin-to-creatinine ratio. However, a total P/C ratio is acceptable if the albumin-to-creatinine ratio is high (> 500 to 1000 mg/g). [51]
Dipstick proteinuria may suggest a glomerular or tubulointerstitial problem. The urine sediment finding of red blood cells (RBCs) and RBC casts suggests proliferative glomerulonephritis. Pyuria and/or white blood cell casts suggest interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection.
Renal Function Formulas
The Cockcroft-Gault formula for estimating creatinine clearance (CrCl) should be used routinely as a simple means to provide a reliable approximation of residual renal function in all patients with CKD. The formulas are as follows:
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CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72)
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CrCl (female) = CrCl (male) × 0.85
Alternatively, the Modification of Diet in Renal Disease (MDRD) Study equation could be used to calculate the glomerular filtration rate (GFR). This equation does not require a patient's weight. [52]
However, the MDRD underestimates the measured GFR at levels above 60 mL/min/1.73 m2. Stevens et al found that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is more accurate than the MDRD Study equation overall and across most subgroups and that it can report estimated GFRs that are at or above 60 mL/min/1.73 m2. [53]
However, a study by Silveiro et al found that both the CKD-EPI and MDRD equations underestimated GFR in patients with type 2 diabetes. [54] The measured GFR was 103 ± 23 mL/min/1.73 m², the CKD-EPI GFR was 83 ± 15 mL/min/1.73 m², and the MDRD GFR was 78 ± 17 mL/min/1.73 m². Accuracy was 67% for the CKD-EPI equation and 64% for the MDRD equation. [54]
Renal function calculation in pediatric patients
GFR in children is calculated using the Schwartz formula (see Chronic Kidney Disease in Children). Because this formula may currently overestimate GFR, likely due to a change in methods used to measure creatinine, Schwartz et al have proposed an updated equation that includes cystatin C. [55] However, the majority of dosing guidelines for medication adjustments due to reduced GFR use the original Schwartz equations.
Renal function calculation in elderly patients
Age is an important consideration with respect to estimated GFR. In a 70-kg man aged 25 years, a serum creatinine value of 1.2 mg/dL represents an estimated GFR of 74 mL/min/1.73m2, but in a 70-kg man aged 80 years, that same value represents an estimated GFR of 58 mL/min/1.73m2. Thus, in a 70-kg, 80-year-old man, a serum creatinine of 2 mg/dL actually represents severe renal impairment, with an estimated GFR of 32 mL/min/1.73 m2 as measured by the MDRD equation.
Therefore, in elderly patients an estimated GFR must be determined using a formula such as the MDRD equation, which includes age as a variable. This will allow appropriate adjustments of drug dosing and avoidance of nephrotoxins, in patients who have more extensive CKD than would be suggested by the serum creatinine value alone.
Renal Ultrasonography
Renal ultrasonography is useful to screen for hydronephrosis, which may not be observed in early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Small, echogenic kidneys are observed in advanced renal failure.
In contrast, kidneys usually are normal in size in advanced diabetic nephropathy, in which affected kidneys are initially enlarged from hyperfiltration. Structural abnormalities, such as those indicative of polycystic kidneys, also may be observed on ultrasonograms.
Renal ultrasonography is the initial imaging modality of choice for children. However, radiologists must have specific training to be able to recognize abnormal kidney size or development in pediatric patients.
Radiography
A retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction exists despite a negative finding on renal ultrasonography. Intravenous pyelography is not commonly performed, because of the potential for renal toxicity from the intravenous contrast; however, this procedure is often used to diagnose renal stones.
Plain abdominal radiography is particularly useful to look for radio-opaque stones or nephrocalcinosis, while a voiding cystourethrogram (VCUG) is the criterion standard for diagnosis of vesicoureteral reflux.
CT, MRI, and Radionuclide Scans
Computed tomography (CT) scanning can better define renal masses and cysts usually noted on ultrasonography. Also, CT scanning is the most sensitive test for identifying renal stones. Intravenous (IV) contrast–enhanced CT scans should be avoided in patients with renal impairment to avoid acute kidney injury; this risk significantly increases in patients with moderate to severe CKD. Dehydration also markedly increases this risk.
Magnetic resonance imaging (MRI) is very useful in patients who would otherwise undergo a CT scan but who cannot receive IV contrast. This imaging modality is reliable in the diagnosis of renal vein thrombosis, as are CT scanning and renal venography.
Magnetic resonance angiography (MRA) is becoming more useful for the diagnosis of renal artery stenosis, although renal arteriography remains the criterion standard. However, MRI contrast is problematic in patients with existing chronic kidney disease (CKD) because they have a low, but potentially fatal, risk of developing nephrogenic systemic fibrosis.
A renal radionuclide scan can be used to screen for renal artery stenosis when performed with captopril administration; it also quantitates differential renal contribution to total glomerular filtration rate (GFR). However, radionuclide scans are unreliable in patients with a GFR of less than 30 mL/min/1.73 m².
Renal Biopsy
Percutaneous renal biopsy is performed most often with ultrasonographic guidance and the use of a spring-loaded or other semi-automated needle. This procedure is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after an appropriate workup.
Biopsies are also indicated to guide management in already-diagnosed conditions, such as lupus, in which the prognosis is highly dependent on the degree of kidney involvement. Biopsy is not usually indicated when renal ultrasonography reveals small, echogenic kidneys on ultrasonography, because this finding represents severe scarring and chronic, irreversible injury.
The most common complication of this procedure is bleeding, which can be life-threatening in a minority of cases. Surgical open renal biopsy can be considered when the risk of renal bleeding is felt to be great, occasionally with solitary kidneys, or when percutaneous biopsy is technically difficult to perform.
Renal histology in CKD reveals findings compatible with the underlying primary renal diagnosis. In some cases, a biopsy may show nonspecific changes, with the exact diagnosis remaining in doubt.
Screening
American College of Physicians guidelines on screening for CKD include the following recommendations:
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Do not screen for CKD in asymptomatic adults without risk factors for CKD (grade: weak recommendation, low-quality evidence).
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Do not test for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II-receptor blocker (ARB)(grade: weak recommendation, low-quality evidence).
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Chronic kidney disease: Calciphylaxis due to secondary hyperparathyroidism.
