Q&A column

Editors: Olga Pozdnyakova, MD, PhD, Geoffrey Wool, MD, PhD, David Bernard, MD, PhD & Raul S. Gonzalez, MD

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Q. What are the preferred tests for chronic kidney disease (CKD) screening and classification?

A. December 2024—Persistent or severe kidney injury, caused by various etiologies, including hypertension, diabetes, cardiovascular disease, nephrolithiasis, autoimmune conditions, and exposure to nephrotoxic drugs, increases a person’s risk of developing CKD.^1,2 With a worldwide prevalence of more than nine percent, CKD is a significant cause of morbidity and mortality.

Early CKD detection and therapeutic intervention reduce the risk of complications and improve patient outcomes. Therefore, annual screening is recommended for at-risk patients. CKD is diagnosed based on the presence of one or more markers of kidney damage, such as albumin in the urine, or a glomerular filtration rate (GFR) of less than 60 mL per minute per 1.73 m² for three or more months.

Urine albumin is a sensitive marker of kidney damage and an essential component of the testing approaches recommended for CKD screening, diagnosis, classification, and prognostic risk assessment. The National Kidney Foundation recommends the use of screening tests that evaluate albuminuria and estimated GFR (eGFR).³ Albuminuria is independently associated with a risk of CKD progression, and reducing albuminuria by 30 percent or more decreases the risk of adverse cardiovascular and renal outcomes in patients with diabetes.⁴

Albuminuria can be assessed by measuring the albumin excretion rate from a 24-hour urine specimen or the urine albumin to creatinine ratio (ACR) from a random, or spot, urine specimen. Due to difficulties with patient compliance for collecting a 24-hour urine specimen, measurement of the ACR on a first morning random specimen is preferred. Urine albumin results should never be reported without calculating the ACR because urine albumin levels can be affected by a person’s hydration status and amount of physical activity as well as the time of specimen collection.⁵

Albuminuria is associated with a higher risk of CKD progression, even if the eGFR is normal (less than 30 mg/g or 3 mg/mmol).¹ An ACR between 30 and 300 mg/g (3–30 mg/mmol) indicates a moderately increased risk of CKD progression, while an ACR greater than 300 mg/g (30 mg/mmol) indicates a severely increased risk. These ACR clinical decision thresholds are typically reported by clinical laboratories. However, a recent meta-analysis showed that ACR values of less than 10 mg/g (1 mg/mmol) are associated with an increased risk of cardiovascular mortality, stroke, heart failure, acute kidney injury, and hospitalization.⁶ Therefore, any elevated ACR result should prompt further patient assessment.

A limitation of using ACR decision thresholds is lack of agreement among urine albumin assays. A study assessing 16 commercially available urine albumin assays found a median difference in albumin concentrations of approximately 40 percent, and the College of American Pathologists accuracy-based urine (ABU) Survey found that differences in reported ACR values are due to albumin measurement, not creatinine.⁷ These differences can be significant enough to adversely affect a patient’s CKD risk classification.

An international effort to improve agreement among manufacturers’ assays is being facilitated by the joint National Institute of Diabetes and Digestive and Kidney Diseases/International Federation of Clinical Chemistry and Laboratory Medicine Working Group for Standardization of Albumin in Urine.⁸ The goal is to implement a reference system that improves agreement and bolsters the use of fixed clinical decision thresholds.

The CAP has initiated efforts to improve the agreement of ACR results. The CAP ABU Survey includes minimally manipulated pooled urine, which is intended to be commutable across assays. Participant urine creatinine results are graded against value assignments traceable to the isotope dilution mass spectrometry reference measurement procedure for creatinine provided by the Centers for Disease Control and Prevention reference laboratory. Participant urine albumin results are graded against all-method mean values. However, value assignment using a reference measurement procedure will be implemented once available.

Although they are not graded in the ABU Survey, ACR results are provided to participants. Laboratories can use ABU Survey results to evaluate agreement of their own urine albumin, creatinine, and ACR results with the target values and determine how their manufacturer’s measurement procedure results compare with those of other vendors. This information can help participating laboratories understand how a patient’s CKD classification and prognosis may vary depending on the assay used and help determine the potential impact of a new measurement procedure implemented by the laboratory.

In conclusion, routine measurement of eGFR and the ACR should be performed for patients at risk for CKD and to stratify CKD risk and monitor CKD therapy. Standardization efforts are underway to improve agreement among urine albumin assays. Laboratories that participate in the CAP ABU Survey can gain insight into how their ACR results compare with those of laboratories using other measurement procedures.

1. Stevens PE, Ahmed SB, Carrero JJ, et al.; Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105(4S):S117–S314.
2. American Diabetes Association Professional Practice Committee. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of care in diabetes—2024. Diabetes Care. 2024;47(suppl 1):S52–S76.
3. National Kidney Foundation. Chronic kidney disease: quality care begins with measurement. https://www.kidney.org/kidney-topics/chronic-kidney-disease-quality-care-begins-measurement.
4. Jun M, Ohkuma T, Zoungas S, et al.; ADVANCE Collaborative Group. Changes in albuminuria and the risk of major clinical outcomes in diabetes: results from ADVANCE-ON. Diabetes Care. 2018;41(1):163–170.
5. Miller WG, Bruns DE, Hortin GL, et al.; National Kidney Disease Education Program-IFCC Working Group on Standardization of Albumin in Urine. Current issues in measurement and reporting of urinary albumin excretion. Clin Chem. 2009;55(1):24–38.
6. Writing Group for the CKD Prognosis Consortium; Grams ME, Coresh J, Matsushita K, et al. Estimated glomerular filtration rate, albuminuria, and adverse outcomes: an individual-participant data meta-analysis. JAMA. 2023;330(13):1266–1277.
7. Bachmann LM, Nilsson G, Bruns DE, et al. State of the art for measurement of urine albumin: comparison of routine measurement procedures to isotope dilution tandem mass spectrometry. Clin Chem. 2014;60(3):471–480.
8. Miller WG, Bachmann LM, Budd J, et al. Extent of equivalence of results for urine albumin among 3 candidate mass spectrometry reference measurement procedures. Clin Chem. 2024;70(11):1375–1382.

Lorin M. Bachmann, PhD, DABCC
Co-Director, Clinical Chemistry
VCU Health
Professor of Pathology
Virginia Commonwealth University
Richmond, Va.
Member, CAP Accuracy-Based Programs Committee

Amy B. Karger, MD, PhD, DABCC
Medical Director, West Bank Laboratory
System Director, Point-of-Care Testing
Director, Biochemical Genetics Laboratory
Professor, Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis, Minn.
Member, CAP Accuracy-Based Programs Committee

Q. Is there a formula to correct a white blood cell count for micromegakaryocytes, or are megakaryocytes considered clinically insignificant unless there are greater than five per 100 WBCs? Is there a movement to drop reporting percents for individual WBCs, reactive lymphocytes, and reticulocytes? If so, does the CAP support such a change?

A. Circulating megakaryocytes (micromegakaryocytes, megakaryoblasts, and bare megakaryocyte nuclei) can be present in the peripheral blood of patients with a suspected or confirmed diagnosis of myeloid neoplasia and, rarely, secondary to nonmalignant etiologies, as well as in healthy neonates.^1,2

Automated hematology analyzers report circulating megakaryocytes as WBCs, resulting in falsely high WBC counts. Manual review of the peripheral blood smear is mandatory to assess the type of cells causing leukocytosis. If circulating megakaryocytes are present, a pathologist review is helpful to evaluate the proportion of these cells and whether the frequency affects the WBC count, as well as to determine their underlying etiology.

Given the rarity of circulating megakaryocytes, a clinically validated cutoff for a corrected WBC count in such scenarios has not been established. Therefore, laboratories may not have a standard operating procedure for addressing circulating megakaryocytes. The literature suggests an arbitrarily defined cutoff of greater than 10 megakaryocytes per 100 WBCs. The following formula can be used to correct the WBC count in the presence of circulating mega­karyocytes.³

Sometimes nucleated red blood cells (nRBCs) and megakaryocytes are present in peripheral blood, especially in myeloid neoplasms. In such instances, the aforementioned formula can be modified to the following.³

With regard to the second question, CAP recommendations have historically supported reporting an absolute WBC count and the corresponding reference intervals over a relative (percentage) WBC count.⁴ Further, an absolute reticulocyte count is a better parameter for evaluating erythropoiesis than a reticulocyte percentage, especially in patients with low hematocrit.⁵ However, CAP proficiency testing requires reporting the WBC differential and reticulocyte count in percent and recommends absolute value reporting when possible to comply with Centers for Medicare and Medicaid Services regulations.

Absolute and/or relative numbers are justified based on the clinical scenario. For example, WBC percentages are often required for diagnosing and classifying hematologic malignancies, such as the percentage of blasts in peripheral blood in acute myeloid leukemia or acute lymphoblastic leukemia. On the other hand, the evaluation of neutropenia is based on the absolute neutrophil count rather than the percent. Another important consideration is the use of percent individual WBC count as a parameter for hematology analyzer flagging, wherein the use of an absolute count could be misleading, especially in the presence of leukocytosis, and result in unnecessary manual slide review. While it is not mandatory to report both relative (percent) and absolute individual WBC counts, it is highly recommended.

1. Garg N, Gupta RJ, Kumar S. Megakaryocytes in peripheral blood smears. Turk J Haematol. 2019;36(3):212–213.
2. Singh P, Chandra D, Gupta R, et al. Circulating micromegakaryocytes; challenges and clues to diagnosis. Indian J Hematol Blood Transfus. 2020;36(2):411–413.
3. Gulati G, Uppal G, Gong J. Unreliable automated complete blood count results: causes, recognition, and resolution. Ann Lab Med. 2022;42(5):515–530.
4. Etzell JE. For WBC differentials, report in absolute numbers. CAP TODAY. 2010;24(3):12.
5. Piva E, Brugnara C, Spolaore F, Plebani M. Clinical utility of reticulocyte parameters. Clin Lab Med. 2015;35(1):133–163.

Aishwarya Ravindran, MD
Assistant Professor of Pathology
Division of Laboratory Medicine, Hematopathology
University of Alabama at Birmingham
Birmingham, Ala.
Member, CAP Hematology/Clinical Microscopy Committee

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Note to readers: We introduce to you this month the four new editors of the Q&A column. They have agreed to succeed the late Frederick Kiechle, MD, PhD, Q&A column editor from 2008 until his death this year (https://bit.ly/CT_1024-FLKiechle), in directing readers’ questions to various experts for answers and approving the answers for publication. Each will provide guidance for the questions that fall into their respective areas of expertise.

Olga Pozdnyakova, MD, PhD, is professor of pathology and laboratory medicine, University of Pennsylvania Perelman School of Medicine, and director of the Division of Hematopathology and medical director of the hematology and flow cytometry laboratories, Hospital of the University of Pennsylvania. She is chair of the CAP Hematology/Clinical Microscopy Committee.

Geoffrey Wool, MD, PhD, is associate professor of pathology and medical director of the coagulation laboratory and blood bank, Department of Pathology, University of Chicago. He is a member of the CAP Hemostasis and Thrombosis Committee.

David Bernard, MD, PhD, is associate professor of pathology and genomic medicine, Academic Institute, and associate clinical member, Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Weill Cornell Medical College. He is medical director of clinical pathology.

Raul S. Gonzalez, MD, is professor of pathology and laboratory medicine, co-director of anatomic pathology research, and director of the gastrointestinal pathology service, Department of Pathology and Laboratory Medicine, Emory School of Medicine. He is chair of the CAP Surgical Pathology Committee.