Biomarkers vs Machines: The Race to Predict Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a serious complication affecting up to 15% of hospitalized patients. Early diagnosis is critical to prevent irreversible kidney damage that could otherwise lead to significant morbidity and mortality. However, AKI is a clinically silent syndrome, and current detection primarily relies on measuring a rise in serum creatinine, an imperfect marker that can be slow to react to developing AKI. Over the past decade, new innovations have emerged in the form of biomarkers and artificial intelligence tools to aid in the early diagnosis and prediction of imminent AKI. CONTENT: This review summarizes and critically evaluates the latest developments in AKI detection and prediction by emerging biomarkers and artificial intelligence. Main guidelines and studies discussed herein include those evaluating clinical utilitiy of alternate filtration markers such as cystatin C and structural injury markers such as neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloprotease 2 with insulin-like growth factor binding protein 7 and machine learning algorithms for the detection and prediction of AKI in adult and pediatric populations. Recommendations for clinical practices considering the adoption of these new tools are also provided. SUMMARY: The race to detect AKI is heating up. Regulatory approval of select biomarkers for clinical use and the emergence of machine learning algorithms that can predict imminent AKI with high accuracy are all promising developments. But the race is far from being won. Future research focusing on clinical outcome studies that demonstrate the utility and validity of implementing these new tools into clinical practice is needed.

The times they are K+-changin': bringing the potassium curriculum out of the 20th century.

PURPOSE OF REVIEW: Although most of the current medical education literature has focused on teaching strategies, little attention has been devoted to selecting appropriate course content. Despite elegant descriptions of physiologic mechanisms in recent decades, medical school curricula and students continue to rely on outdated textbooks and certification examination study aids composed to fit an antiquated exam blueprint. RECENT FINDINGS: Advances in our understanding of potassium physiology offer multiple examples of key concepts that deserve to be included in the modern-day renal physiology curriculum, including the relationship of potassium to blood pressure and the potassium 'switch', the aldosterone paradox, and novel pharmacologic agents that target dietary potassium absorption and potassium handling in the kidney. SUMMARY: Key advances in our understanding and application of renal physiology to patient care have not been readily integrated into the nephrology curriculum of medical students. Difficult questions remain regarding when new concepts are sufficiently established to be introduced to medical students in the preclinical years.

Biology of the proximal tubule in body homeostasis and kidney disease.

The proximal tubule (PT) is known as the workhorse of the kidney, both for the range and magnitude of the functions that it performs. It is not only responsible for reabsorbing most solutes and proteins filtered by glomeruli, but also for secreting non-filtered substances including drugs and uremic toxins. The PT therefore plays a pivotal role in kidney physiology and body homeostasis. Moreover, it is the major site of damage in acute kidney injury and nephrotoxicity. In this review, we will provide an introduction to the cell biology of the PT and explore how it is adapted to the execution of a myriad of different functions and how these can differ between males and females. We will then discuss how the PT regulates phosphate, glucose and acid-base balance, and the consequences of alterations in PT function for bone and cardiovascular health. Finally, we explore why the PT is vulnerable to ischemic and toxic insults, and how acute injury in the PT can lead to maladaptive repair, chronic damage, and kidney fibrosis. In summary, we will demonstrate that knowledge of the basic cell biology of the PT is critical for understanding kidney disease phenotypes and their associated systemic complications, and for developing new therapeutic strategies to prevent these.

Limited Evidence for Use of a Black Race Modifier in eGFR Calculations: A Systematic Review.

BACKGROUND: Commonly used estimated glomerular filtration rate (eGFR) equations include a Black race modifier (BRM) that was incorporated during equation derivation. Race is a social construct, and a poorly characterized variable that is applied inconsistently in clinical settings. The BRM results in higher eGFR for any creatinine concentration, implying fundamental differences in creatinine production or excretion in Black individuals compared to other populations. Equations without inclusion of the BRM have the potential to detect kidney disease earlier in patients at the greatest risk of chronic kidney disease (CKD), but also has the potential to over-diagnose CKD or impact downstream clinical interventions. The purpose of this study was to use an evidence-based approach to systematically evaluate the literature relevant to the performance of the eGFR equations with and without the BRM and to examine the clinical impact of the use or removal. CONTENT: PubMed and Embase databases were searched for studies comparing measured GFR to eGFR in racially diverse adult populations using the Modification of Diet in Renal Disease or the 2009-Chronic Kidney Disease Epidemiology Collaboration-creatinine equations based on standardized creatinine measurements. Additionally, we searched for studies comparing clinical use of eGFR calculated with and without the BRM. Here, 8632 unique publications were identified; an additional 3 studies were added post hoc. In total, 96 studies were subjected to further analysis and 44 studies were used to make a final assessment. SUMMARY: There is limited published evidence to support the use of a BRM in eGFR equations.

Removal of the Black race coefficient from the estimated glomerular filtration equation improves transplant eligibility for Black patients at a single center.

Race is a social construct that cannot be measured, can be used imprecisely and may contribute to disparities in kidney transplant access for Black patients. At Beth Israel Deaconess Medical Center, we dropped the Black race coefficient in the estimated glomerular filtration rate (eGFR) report in 2017. We conducted a quality improvement project to examine the impact of this change. Before the change, only 26% of our Black patients were listed for preemptive transplant compared to 70% of White patients. Since the change, we found a steady increase in the percentage of Black patients listed before starting dialysis. The average eGFR at listing prior to 2017 was significantly lower in Black patients but after, there was no longer a significant difference. Nine patients "gained" an average of 457 days of wait time directly related to discarding the Black race coefficient. Increased time on the list prior to dialysis initiation allows for evaluation of potential live donors and improves the possibility of a pre-emptive live or deceased donor transplant and allows for a shorter period on dialysis before transplant. In this single center initiative, we demonstrate the benefit of discarding race from the eGFR report for Black patients awaiting kidney transplantation.

Case report: extreme coronary calcifications and hypomagnesemia in a patient with a 17q12 deletion involving HNF1B.

BACKGROUND: 17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described. CASE PRESENTATION: We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification. CONCLUSION: Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.

Share your passion for nephrology: ten tips to invigorate attending rounds and precepting sessions.

Although there have been mounting concerns over the decline in applicants to nephrology training programs, strategies to entice students and trainees to pursue a career in nephrology are lacking. Furthermore, the complex factors that contribute to career decisions and the lag between a positive interaction and a decision to pursue nephrology make such strategies difficult to assess. Nevertheless, it is still important to continue efforts to mentor and inspire. This article offers 10 strategies to help nephrologists share passion for nephrology in the clinical arena. These include the excitement of the dialysis unit, ethical dilemmas, pearls for the bedside, and questions "on the fly."

Advances in the management of chronic kidney disease.

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.

Acid Base Disorders in Cirrhosis.

Metabolic and respiratory acid-base disorders are common in individuals with liver disease and cirrhosis. The most common disorder is respiratory alkalosis, which may be related to dyspnea or respiratory stimulation. Primary metabolic disorders are less common. Although the liver plays a role in metabolism of amino acids and generation of acid from dietary sources, it does not play a role in the regulation of pH. Instead, metabolic disorders may arise from alterations in normal metabolism or from medications, particularly diuretics and osmotic laxatives, used in the treatment of these complex patients. Understanding the mechanistic underpinnings of these disorders can aid in the management of individuals with liver disease in the hospital and in outpatient settings.

Metabolic Health Immersion for Medical Education: A Pilot Program with Continuous Glucose Monitors in Medical and Dental Students.

Diet-related chronic diseases are increasing in prevalence and poised to dominate the future careers of current medical students. While the value of nutritionally-informed care and nutrition-based health interventions is increasingly recognized, nutrition education is inconsistently and often inadequately included in medical school curricula. One obstacle to incorporating nutrition into medical and dental school curricula is the density of existing coursework, with incorporation of new material necessitating removal of other material. One solution is to engage students outside the classroom in immersive education in nutrition and metabolism using health-wearables. We report the Metabolic Health Immersion for Medical Education pilot program, spearheaded and designed by Harvard Medical students centering on use of continuous glucose monitors (CGM). Students reported enjoyment with the study, felt encouraged to improve health behaviors, and shared that the experience enhanced their understanding of nutrition and metabolism, was valuable to their medical education, and would influence their future patient care. This study demonstrates proof-of-principle that metabolic health immersion opportunities for health care trainees provide a means of helping to address the current deficit in medical school nutrition education.

AACC/NKF Guidance Document on Improving Equity in Chronic Kidney Disease Care.

BACKGROUND: Kidney disease (KD) is an important health equity issue with Black, Hispanic, and socioeconomically disadvantaged individuals experiencing a disproportionate disease burden. Prior to 2021, the commonly used estimated glomerular filtration rate (eGFR) equations incorporated coefficients for Black race that conferred higher GFR estimates for Black individuals compared to non-Black individuals of the same sex, age, and blood creatinine concentration. With a recognition that race does not delineate distinct biological categories, a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the CKD-EPI 2021 race-agnostic equations. CONTENT: This document provides guidance on implementation of the CKD-EPI 2021 equations. It describes recommendations for KD biomarker testing, and opportunities for collaboration between clinical laboratories and providers to improve KD detection in high-risk populations. Further, the document provides guidance on the use of cystatin C, and eGFR reporting and interpretation in gender-diverse populations. SUMMARY: Implementation of the CKD-EPI 2021 eGFR equations represents progress toward health equity in the management of KD. Ongoing efforts by multidisciplinary teams, including clinical laboratorians, should focus on improved disease detection in clinically and socially high-risk populations. Routine use of cystatin C is recommended to improve the accuracy of eGFR, particularly in patients whose blood creatinine concentrations are confounded by processes other than glomerular filtration. When managing gender-diverse individuals, eGFR should be calculated and reported with both male and female coefficients. Gender-diverse individuals can benefit from a more holistic management approach, particularly at important clinical decision points.

What's Old Is New Again: Harnessing the Power of Original Experiments to Learn Renal Physiology.

Although medical schools across the United States have updated their curricula to incorporate active learning techniques, there has been little discussion on the nature of the content presented to students. Here, we share detailed examples of our experience in using original experiments to lay the groundwork for foundational concepts in renal physiology and pathophysiology. We believe that this approach offers distinct advantages over standard case-based teaching by (1) starting with simple concepts, (2) analyzing memorable visuals, (3) increasing graphical literacy, (4) translating observations to "rules," (5) encouraging critical thinking, and (6) providing historical perspective to the study of medicine. Although we developed this content for medical students, we have found that many of these lessons are also appropriate as foundational concepts for residents and fellows and serve as an excellent springboard for increasingly complex discussions of clinical applications of physiology. The use of original experiments for teaching and learning in renal physiology harnesses skills in critical thinking and provides a solid foundation that will help learners with subsequent case-based learning in the preclerkship curriculum and in the clinical arena.

More than meets the I(ris): Use of manual urine microscopy to complement automated findings in acute kidney injury.

Evaluation of patients with acute kidney injury requires comprehensive assessment that includes a urinalysis, which features both semi-quantitative assessment with a urine dipstick and urine microscopy. This process is labor intensive for clinical laboratories, and availability of excellent automated instruments for urinalysis has prompted utilization and acceptance of this strategy by both by laboratories and clinicians. Recently, however, interest in provider performed microscopy has enjoyed a renaissance thanks to both improved microscopy techniques and the endorsement from social media in nephrology. Here, we present two cases of acute kidney injury in which manual microscopy added valuable information to the automated microscopy.

Decreasing the Lower Limit of Quantitation for Urine Albumin Improves Clinical Utility.

BACKGROUND: Urine albumin-to-creatinine ratio (uACR) is a screening assay for chronic kidney disease (CKD). A value of >30 mg/g is flagged abnormal, but lower ratios have prognostic implications. Thus, to maximize diagnostic utility, urine albumin (uAlb) should be measurable to 3 mg/L to match the lowest creatinine concentration generally utilized (10 mg/dL). Most uAlb assays have lower limits of quantitation (LLOQs) 2- to 4-fold higher. We sought to determine the performance characteristics of a commonly used uAlb assay at 3 mg/L and to evaluate the clinical screening impact of reducing the LLOQ. METHODS: Urine was serially diluted to assess uAlb linearity and precision for concentrations near the claimed LLOQ (12 mg/L). Samples (n = 30) with uAlb <12 mg/L were compared between laboratories. Sequential samples (n = 1239) were evaluated for clinical impact of reducing the measuring range to 3 mg/L. RESULTS: The assay was linear to 1.6 mg/L. Interday precision at 3.7 mg/L and 4.3 mg/L was 7.7% and 8.6%, respectively. Minimal bias was observed between labs (y = 1.091x - 0.75; average bias = -0.13 mg/L). Clinical validation demonstrated 501 of 1239 samples (40.4%) had uAlb <12 mg/L. Using 11.9 mg/L as the numerator for samples with uAlb <12 mg/dL and urine creatinine >10 mg/L, 107 of 499 (21.4%) would have a ratio flagged abnormal at >30 mg/g. Using the numeric value for these samples to 3 mg/L reduced alarm to <1%. CONCLUSIONS: A uAlb LLOQ of 3 mg/L improves screening utility of uACR by simplifying reporting and clinical interpretation when uAlb is low and provides clinical information for prognostic tools developed for people at risk of CKD.

AACC Guidance Document on Laboratory Investigation of Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a sudden episode of kidney damage or failure affecting up to 15% of hospitalized patients and is associated with serious short- and long-term complications, mortality, and health care costs. Current practices to diagnose and stage AKI are variable and do not factor in our improved understanding of the biological and analytical variability of creatinine. In addition, the emergence of biomarkers, for example, cystatin C, insulin-like growth factor binding protein 7, and tissue inhibitor of metalloproteinases 2, and electronic notification tools for earlier detection of AKI, highlights the need for updated recommendations to address these developments. CONTENT: This AACC Academy guidance document is intended to provide laboratorians and clinicians up-to-date information regarding current best practices for the laboratory investigation of AKI. Topics covered include: clinical indications for further investigating potential AKI, analytical considerations for creatinine assays, the impact of biological variability on diagnostic thresholds, defining "baseline" creatinine, role of traditional markers (urine sodium, fractional excretion of sodium, fractional excretion of urea, and blood urea-to-creatinine ratio), urinary microscopic examination, new biomarkers, improving AKI-associated test utilization, and the utility of automated AKI alerts. SUMMARY: The previous decade brought us a significant number of new studies characterizing the performance of existing and new biomarkers, as well as potential new tools for early detection and notification of AKI. This guidance document is intended to inform clinicians and laboratorians on the best practices for the laboratory investigation of AKI, based on expert recommendations where the preponderance of evidence is available.